Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

Introduction

The endoplasmic reticulum (ER), an organelle in most eukaryotic cells, is the foundation for synthesizing several essential substances, including proteins, lipids, and sugars, in addition to nucleic acids. 1 Furthermore, the ER consists of a series of lamellar vesicles and tubular lumens, forming a continuous reticular system that links the nucleus, cytoplasm, and cell membrane, thereby facilitating the transport of substances. 2 Almost all proteins originate in the cytoplasmic matrix and are shortly thereafter translocated to the ER. Specifically, most secreted and transmembrane proteins, including those involved in synthesis, folding, and maturation, begin traveling within the ER lumen. Once appropriately modified, these proteins are either transported to their specific destinations within the cell or released outside through the cell membrane. 3 However, the process of generating proteins does not necessarily proceed in the right direction, and a variety of intrinsic and extrinsic factors may induce ER stress, which is characterized by excessive accumulation of misfolded or unfolded proteins as well as dysregulation of sterol and lipid levels. 4 Mild ER stress can be restored to protein homeostasis by some intracellular processing capacity. Nevertheless, if stress persists beyond the adaptive capacity of the cell, ER stress will activate the unfolded protein response (UPR). This adaptive signaling pathway reduces the burden on unfolded or misfolded proteins, thereby restoring the balance of proteins. 5 When ER stress is extremely severe or persists for too long, it exceeds the adaptive capacity of the cell and may initiate an apoptotic program. 6 Although ER stress usually triggers the UPR, whether the UPR promotes cellular adaptation back to normal or initiates cell death depends on various factors.

Researchers have used ER stress in clinical applications to treat numerous types of diseases because of an understanding of its mechanisms. Growing evidence suggests that the ER stress response can influence the cellular phenotypes critical for cancer onset, progression, and treatment. 7 On the one hand, if the ER stress response that persists in tumor cells is targeted to be induced, leading to their death, this would help prevent cancer progression. 8 On the other hand, inhibiting UPR signaling to enhance antitumor immune responses could make the ER stress response system a potential target for cancer immunotherapy. 9 Cardiovascular diseases are often affected by the accumulation of unfolded or misfolded proteins in the ER, leading to cellular damage that causes cardiovascular dysfunction. 10 Cardiovascular disease is triggered by an imbalance in ER homeostasis, which in turn disrupts the function of the secretory pathway, leading to exacerbation of the ER stress response. ER stress is a critical contributor to the pathogenesis of neurodegenerative diseases, as it disrupts protein folding and impairs neuronal survival. 11 This stress activates the UPR, which, when overwhelmed, leads to neuronal apoptosis and neuroinflammation. The resulting cellular dysfunction is closely associated with cognitive decline and neurodegeneration. ER stress plays a pivotal role in the dysregulation of lipid and glucose homeostasis in metabolic diseases, leading to insulin resistance (IR) and metabolic dysfunction. 12 The accumulation of misfolded proteins within the ER triggers the UPR, further exacerbating metabolic disturbances. This interplay contributes to the progression of various metabolic diseases and associated complications. ER stress is also implicated in the pathogenesis of autoimmune diseases, where it can increase the activation of immune cells and promote the secretion of proinflammatory cytokines. 13 The UPR is activated in response to ER stress, increasing antigen presentation and autoimmune reactivity. This process ultimately results in tissue damage and the exacerbation of autoimmune responses. Therefore, given the role of ER stress in disease pathogenesis, understanding its complex mechanisms in cells of various tissues is important for studying disease pathogenesis and therapeutic strategies.

This review systematically focuses on characterizing ER stress in multiple disease states and explores therapeutic strategies to target ER stress. First, we describe the major research findings in the relevant fields. Next, ER stress-related regulators and their functional mechanisms are described in detail. We subsequently investigated the role of ER stress in five typical disease categories, namely, cancer, cardiovascular disease, neurodegenerative disease, metabolic disease, and autoimmune disease. In addition, we emphasize the feasibility of targeting ER stress as a therapeutic agent and the current status of clinical trials. Finally, we profile several novel drugs for treating ER stress and suggest possible gaps in the current research. We believe that this review will deepen our understanding of the mechanisms of ER stress and elucidate its regulatory functions in human cells during disease progression, thereby improving the efficacy of therapies targeting ER stress.

History and milestones of ER stress research

ER stress is an important mechanism by which cells respond to environmental changes and physiological stress. As an important organelle in the cell, the ER is responsible for synthesizing, folding, and modifying proteins and is also involved in lipid synthesis and calcium storage functions. When cells encounter unfavorable environments (e.g., hypoxia, nutritional deficiencies, pathogen infections, etc.) or intrinsic defects (e.g., protein-folding errors), the function of the ER may be impaired, leading to ER stress. It affects cell survival and is closely related to the occurrence and development of many diseases.

In 1977, scientists first discovered glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), and focused on characterization in the ER. 14 Research on ER stress began in the 1990s, with initial studies focusing on how ER dysfunction affects the physiological state of cells. 15 In 1992, the discovery of transcription factors associated with ER stress opened the study of the UPR. 16 Three key proteins involved in the UPR were successively discovered in mammalian cells from 1998--1999. 17 – 19 These discoveries laid the foundation for subsequent studies revealing the important effects of ER stress on processes such as cell survival, death, and autophagy. Immediately afterward, the first functional study linking ER stress to neurodegenerative diseases reported that neurons are less tolerant to ER stress and that sustained activation is closely associated with neuronal apoptosis. 20

In 2002, with further research, the role of ER stress in cancer was gradually recognized. 21 Tumor cells usually experience high levels of ER stress in the microenvironment because they need to synthesize large amounts of proteins for rapid proliferation. The UPR helps tumor cells adapt to this stress to some extent, but prolonged ER stress may lead to cell death. Therefore, many researchers have focused on promoting tumor cell death by regulating the ER stress response. Research in this area has provided new ideas for cancer treatment. In 2004, research on ER stress made significant advances in a variety of diseases. First, ER stress was found to be a central feature of peripheral insulin resistance and type 2 diabetes mellitus, which play important roles in insulin secretion and fat metabolism. 22 Metabolic diseases can lead to ER dysfunction and affect insulin synthesis and secretion. Research in this area has provided new ideas for the treatment of metabolic diseases such as diabetes, suggesting that improving ER function may help to restore a normal metabolic state. In addition, ER stress is associated with cardiovascular diseases, and long-term stress can lead to cardiomyocyte apoptosis during the progression from cardiac hypertrophy to failure, suggesting that regulating ER stress may be a therapeutic strategy for cardiovascular diseases. 23 Furthermore, ER stress was first found to be associated with autoimmune diseases by studying the antibody response to the human stress protein BiP in patients with rheumatoid arthritis (RA). 24 Studies have shown that ER stress is involved in inflammatory responses and immune cell dysfunction and may lead to autoantigen exposure, which triggers an autoimmune response.

In 2006, drugs targeting ER stress-related pathway inhibitors were first developed, such as 4-phenyl butyric acid (4-PBA), which was used to treat Parkinson’s disease (PD). 25 In 2007, Lin’s team revealed differences in the dynamics of different signaling branches in the ER stress-triggered UPR. The activities of IRE1 and ATF6 decrease under sustained stress, whereas the PERK pathway, including the sustained expression of the proapoptotic factor CCAAT/enhancer-binding protein homologous protein (CHOP), remains active, leading to a shift in the cellular response from protection to apoptosis. Cell survival was significantly enhanced by artificially prolonging IRE1 activity, suggesting that temporal regulation of UPR signaling is critical in determining cell life and death. 26 In 2008 and 2009, two studies revealed a novel mechanism linking ER stress to obesity. Overnutrition triggers obesity by inducing ER stress in the hypothalamus and activating the IKKβ/NF-κB signaling pathway, leading to central insulin and leptin resistance. 27 Reducing ER stress through genetic intervention or chemical chaperones (e.g., PBA and TUDCA) significantly restores leptin sensitivity and ameliorates obesity, and these studies suggest that targeting ER stress is a novel strategy for the treatment of obesity and related metabolic diseases. 28

In 2010, new progress was made in the application of ER stress in tumor therapy. In the hypoxic environment of tumors, ER stress transcriptionally activates the autophagy genes MAP1LC3B and ATG5 through the PERK/CHOP signaling axis, which enhances the hypoxia tolerance and radioresistance of tumor cells. 29 In 2011, a novel IRE1 small molecule inhibitor, STF-083010, was developed for the treatment of multiple myeloma (MM) and has shown significant antitumor activity. 30 In 2012, a PERK inhibitor, GSK2606414, and two IRE1 inhibitors, 4μ8C and MKC3946, were developed for the treatment of cancer. 31 – 33 In 2014, two more IRE1 inhibitors were manufactured, with B-I09 showing significant therapeutic efficacy in a variety of hematologic tumors and KIRA6 playing a role in the treatment of metabolic diseases. 34 , 35 In 2015, AMG-44 was developed as a highly potent and selective PERK inhibitor that targets and alleviates ER stress-associated pathological processes by sensing the UPR and inhibiting its activity, providing novel tool compounds for the treatment of diseases such as cancer. 36 In 2017, a major breakthrough was made in the treatment of type 1 diabetes by targeting ER stress; attenuating IRE1 reduces pancreatic β-apoptosis and reverses type 1 diabetes (T1D). The IRE1 inhibitor KIRA8 was also effective in reversing established diabetes by preserving the physiological function of β-cells. 37 In 2019, the IRE1-specific inhibitor MKC8866 strongly inhibited prostate cancer tumor growth and showed synergistic antitumor effects with current drugs. 38

In 2021, a novel pancreatic cancer therapeutic agent, YUM70, was developed with the primary function of inducing ER stress-mediated apoptosis in tumor cells by inhibiting GRP78. 39 In 2022, a breakthrough in tumor therapy was achieved when a novel tumor vaccine against ER stress began to be put into clinical trials as an active immunotherapy. 40 In 2023, Benson’s team discovered that the gut flora metabolite trimethylamine N-oxide (TMAO) exacerbates the progression of abdominal aortic aneurysm (AAA) through activation of the PERK/eIF2α/ATF4/CHOP axis, enhances apoptosis, and inhibits autophagy in vascular smooth muscle cells. Therefore, targeted inhibition of TMAO generation effectively attenuates ER stress and suppresses aneurysm pathology. 41 In 2024, Xu et al. revealed that the ER stress sensor IRE1 silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD), thereby suppressing NLRP3 inflammasome-mediated pyroptosis in triple-negative breast cancer. Inhibition of IRE1 RNase activity restored dsRNA accumulation, triggering pyroptosis and the conversion of immunologically cold tumors into immunogenic tumors, increasing the efficacy of chemoimmunotherapy. 42 In summary, ER stress, a key biological process, is closely related to the occurrence and development of many diseases. By revealing the mechanism of ER stress and exploring its role in cancer, cardiovascular diseases, metabolic diseases, neurodegenerative diseases, and autoimmune diseases, researchers have provided new directions for future therapeutic strategies (Fig. 1 ). Fig. 1 Timeline of ER stress-related research. The timeline summarizes key findings and developments in ER stress-related research, demonstrating the ongoing progress and innovation in this field. The key protein involved in ER stress, BiP/GRP78, was discovered for the first time in 1977. The UPR can subsequently help cells adapt to this stress to some extent, but prolonged ER stress can also lead to cell death. Three key proteins involved in the UPR were successively discovered in mammalian cells from 1998--1999. Thus, ER stress has been shown to play an important role in various types of diseases. Drugs that target inhibitors of ER stress-related pathways were developed in 2006. In the following decade, an increasing number of ER stress-related pathway inhibitors, the most commonly used of which include B-I09, GSK2606414, ISRIB, and 4μ8C, were used in clinical therapy. Currently, ER stress pathway inhibitors are widely used, and novel tumor vaccines targeting them have been successfully developed

Signaling pathways and regulatory mechanisms of ER stress

ER stress is a cellular response that occurs when ER function is compromised or when the ER load exceeds normal capacity and has emerged as a key factor in the pathogenesis of numerous diseases. The ER is vital for protein synthesis and folding, calcium ion transport, and energy metabolism. However, various stimuli, such as nutrient deprivation, oxidative stress, and pathological conditions, can disrupt ER function, resulting in the accumulation of misfolded proteins. This triggers the unfolded protein response (UPR), a complex signaling network that aims to restore ER homeostasis. Understanding the underlying causes of ER stress, its downstream signaling factors, and regulatory pathways is essential for elucidating its role in various diseases. This knowledge provides insights into disease mechanisms and offers potential therapeutic targets for intervention. The following sections explore these aspects in detail, shedding light on the multifaceted role of ER stress in health and disease.

Unfolded protein response signaling pathways

As an adaptive cellular response to ER stress, the UPR is activated to restore homeostasis at the cellular level when impaired ER function results in the accumulation of unfolded or misfolded proteins. 43 In 1977, researchers discovered that excessive glucose consumption led to cessation or significant inhibition of protein synthesis, a phenomenon not fully understood until the UPR was recognized in 1992. 14 , 15 The mammalian UPR pathway is composed of three central signaling cascades (inositol-requiring protein 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase R-like ER kinase (PERK)) activated by transmembrane sensors in the ER, which coordinate responses to the harmful accumulation of unfolded or misfolded proteins. 44 BiP/GRP78 acts as a molecular chaperone protein within the ER that binds and releases the three UPR sensors on the ER membrane. 45 Under normal conditions, BiP binds to these sensors and keeps them inactive. Nevertheless, when there is an increase in unfolded proteins within the ER, BiP dissociates from some of the binding sites in these sensors, thereby activating them and initiating the UPR response (Fig. 2 ). Fig. 2 Causes of the ER stress response and the triggering process of the UPR. The ER consists of a series of lamellar vesicles and tubular lumens, forming a continuous reticular system that links the nucleus, cytoplasm, and cell membrane. Many endogenous and exogenous cellular factors contribute to ER dysfunction in cancer cells, including abnormal protein synthesis, calcium imbalance, genetic alterations, dysfunction of mitochondria, lack of oxygen, nutrient availability, acidic pH, oxidative stress, and therapy status. These factors contribute to the ER stress response. As an adaptive cellular response to ER stress, the UPR is activated to restore homeostasis at the cellular level when impaired ER function results in the accumulation of unfolded or misfolded proteins. Three of the most classical genes in the UPR are IRE1, ATF6, and PERK. When GRP78, also known as BiP, releases the three UPR sensors in the ER membrane, they act synergistically through different mechanisms in response to the accumulation of unfolded proteins. IRE1, a receptor kinase on the ER membrane, is activated when unfolded proteins accumulate in the ER. Upon UPR activation, IRE1 dimerizes and autophosphorylates, activating its RNase domain. This leads to the excision of a 26-nucleotide fragment from XBP1 mRNA, producing spliced XBP1 mRNA that encodes the active XBP1 protein. Spliced XBP1 then activates genes that aid in restoring ER function. Moreover, IRE1 RNase modulates RIDD to selectively degrade ER-associated mRNAs, affecting protein folding. ATF6 is translocated from the ER membrane to the Golgi during the accumulation of unfolded proteins, where it is cleaved to form small fragments of active ATF6 called ATF6αp50. This small fragment can enter the nucleus and facilitate the transcription of genes related to protein folding, such as those that enhance the folding function of molecular chaperones and the ER, helping to restore normal protein function. PERK, a kinase located on the ER membrane, inhibits global protein synthesis by phosphorylating eIF2α upon activation. This process reduces overall translation, allowing the ER more time and resources to address misfolded proteins while also preferentially translating specific protective mRNAs, such as ATF4, to alleviate the ER burden. In addition, during ROS-mediated ER stress, PERK contributes to apoptosis by maintaining proapoptotic CHOP levels when ER stress cannot be relieved

IRE1, a crucial upstream transmembrane protein for the ER stress response, was identified in mammals in 1993. 46 Upon UPR activation, IRE1 dimerizes and undergoes autophosphorylation, which activates its RNase structural domain through conformational changes. 47 The excision of a 26-nucleotide fragment from X-box binding protein 1 (XBP1) mRNA on the cell membrane results in spliced XBP1 mRNA that encodes the active XBP1 protein. 48 XBP1 activates several genes associated with protein folding, ER-associated degradation (ERAD), and lipid synthesis, thereby helping cells restore ER function. 49 Under severe ER stress, sustained activation of IRE1 enhances the XBP1-dependent expression of the classical UPR gene, which may promote cell injury. 50 Recent studies have shown that IRE1 RNase modulates RIDD to selectively degrade ER-associated mRNAs, affecting the protein-folding load, cellular metabolism, inflammation, and inflammasome signaling. 51 Moreover, prolonged activation of IRE1 can promote cell death by activating apoptotic pathways such as the c-Jun N-terminal kinase (JNK) pathway. 52

ATF6, which was first isolated in 1998 via a yeast one-hybrid screen, is considered a putative ER stress-binding protein. 17 Under non-ER stress conditions, ATF6 and BiP form a stable complex in the ER, with BiP inhibiting glutaminase (GLS). Upon activation, the N-terminal fragment of ATF6 is translocated to the nucleus, where it promotes the transcription of genes with ER stress response elements and those targeted by the UPR. 53 ATF6 regulates the expression of a series of key genes in the ER homeostasis network, which encode proteins that contribute to cellular stress resistance and thus protect cells from damage. 54 Moreover, given the overlapping functions of IRE1 and ATF6α, some ATF6α targets are also regulated by XBP1, although this influence is less significant than that of IRE1 in ER stress. 55 XBP1 and ATF6p50 induce changes in the structure and function of the ER, contributing to the phenotype of professional secretory cells by expanding the surface area of the ER to support cellular functions during ER stress. 56

PERK was identified in 1999 and features a luminal structural domain akin to that of IRE1, which senses ER stress. 57 The signature role of PERK is to phosphorylate eIF2α and inhibit protein synthesis, thereby coregulating the integrated cellular stress response. 55 PERK inhibits global translation by phosphorylating the translation factor eIF2α, which preferentially translates certain protective mRNAs (e.g., ATF4) to reduce the ER burden. Recent findings indicate that ER whorl formation, an ER stress effector mechanism, depends on PERK kinase activity and the coat protein complex II (COPII) mechanism, aiding in ER stress-induced translational repression. 58 By inhibiting protein synthesis, PERK reduces the entry of new proteins into the ER, thereby relieving the burden on the ER. In addition, PERK activates other signaling pathways, such as antioxidative stress and apoptosis regulation, to help cells adapt to stressful environments. During reactive oxygen species (ROS)-mediated ER stress, when ER stress cannot be reversed, PERK contributes to apoptosis by maintaining proapoptotic CHOP levels and facilitating the propagation of ROS signals between the ER and mitochondria. 59

Upstream regulators of ER stress

The ER contains many chaperone proteins, glycosylases, and oxidoreductases, creating an optimal environment for folding nascent peptide chains. 60 Factors such as abnormal protein synthesis, calcium imbalance, genetic and epigenetic factors, mitochondrial dysfunction, a lack of oxygen, reduced nutrient availability, acidic pH, oxidative stress, and tumor therapy collectively contribute to the ER stress response (Fig. 2 ).

Abnormal protein synthesis

Abnormal protein synthesis is the primary cause of ER stress. Typically, newly synthesized proteins undergo complex folding to ensure their correct three-dimensional conformation. 61 When molecular chaperone proteins in the ER, such as BiP/GRP78, are damaged or do not function, the cell fails to correctly fold proteins. 57 This leads to missynthesis of proteins in the ER and subsequent initiation of the ER stress state to mitigate ER damage. In addition, blockage of protein degradation pathways can also lead to excessive protein accumulation and activate ER stress, the most common of which is the ubiquitin‒proteasome pathway. 62 The epithelial‒mesenchymal transition (EMT) process involves the synthesis and secretion of large amounts of extracellular matrix proteins, which affect the protein secretion rate, leading to protein accumulation and triggering ER stress responses. 63 Since the ER cannot be generated de novo, proliferating cancer cells necessitate rapid ER expansion or division to distribute to daughter cells. These findings suggest that the protein synthesis rate is a crucial driver of ER stress and tumorigenicity in vivo. 64

Calcium imbalance

The ER is an important calcium ion reservoir in the cell that regulates calcium ion uptake, storage, and signaling. 65 Hence, disturbances in calcium ion homeostasis are among the most common factors contributing to the development of ER stress. 66 Elevated levels of calcium ions in the cytoplasm under pathological conditions induce the activation of proteases, lipases, and nucleases. 67 When calcium adenosine triphosphatase (ATPase), such as Sarco/(endo) plasmic reticulum Ca2+ ATPase, is pumped into the ER, it leads to abnormal loss or release of calcium ions. 68 Leakage of calcium ions directly affects the calcium concentration within the ER, causing the internal environment to become unstable and affecting the normal folding of proteins. When the ER senses this instability, the ER stress response is initiated. Collins et al. reported that deletion of sensor substrate interaction molecule 1 (STIM1), which stores calcium ions, leads to age-dependent ER stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. 69 During calcium ion transfer, impaired function, overactivation, or aberrant expression of channels between the ER and the cytoplasm (inositol 1,4,5-trisphosphate receptor) leads to uncontrolled opening or closing of the channels, thereby disrupting ER calcium ion homeostasis. 70 Importantly, calcium-binding proteins play a critical role in ensuring proper protein folding. Calnexin is a calcium-binding protein in the ER membrane that interacts with specific glycosylated proteins and promotes proper folding. 71 Calreticulin (CALR), another common calcium-binding protein, is extensively involved in biological processes such as ER calcium homeostasis and protein processing. It is involved in recognizing and repairing incompletely folded or misfolded proteins together with related molecular chaperones such as GRP78. 72 If CALR malfunctions, this process may be affected, causing misfolded proteins to fail to be repaired or degraded in time, which in turn causes ER stress. 73 Moreover, calcium ions may leak from the ER due to mutations, changes in the extracellular environment, or exposure to drugs or toxins, disrupting homeostasis and initiating ER stress. 74 Unfortunately, no studies have clarified the quantitative relationship between calcium signaling and ER stress, which requires further exploration.

Genetic and epigenetic factors

A variety of genetic and epigenetic factors influence the occurrence of ER stress. Genetic factors are characteristics and mechanisms directly determined by genes, and they influence the occurrence of ER stress through gene expression and regulation. Genetic defects in ER proteins promote the formation of misfolded proteins, inducing ER stress, which leads to disease. Functional defects in molecular chaperones or folding enzymes directly impair the protein-folding capacity of the ER, leading to the accumulation of unfolded proteins. Mutations in the folding enzyme PARK7 lead to mitochondrial dysfunction, affecting ER calcium homeostasis through mitochondria‒ER contact sites (MAMs) and leading to persistent activation of ER stress. 75 In addition, aberrant proteins produced by gene mutations may fail to pass through the ER quality control (ERQC) system and persistently activate ER stress. Lee et al. demonstrated that mutations in ChEL impaired thyroglobulin folding, which prevented thyroglobulin from leaving the ER and induced ER stress. 76

In tumor studies, malignant transformation requires a multistage reaction and the accumulation of genetic mutations that decouple proliferative capacity from extracellular regulation and growth factor-mediated regulation. 77 Specifically, the loss of tumor suppressors and the overexpression of oncogenes can significantly increase the rate of protein synthesis, meeting the heightened metabolic demands of tumorigenesis. 78 Oncogenic transformation dramatically increases the rate of protein synthesis, leading to ER stress, and the deletion of tumor suppressors such as p53 and phosphatase and tensin homolog (PTEN) is a major driver. 79 Loss of the tumor suppressor complex proteins tuberous sclerosis complex 1 (TSC1) and TSC2 has also been shown to activate the UPR in a cell-autonomous manner. 80 In addition, oncogenic BRAF-mediated p38 activation in melanoma stimulates the IRE1/apoptosis signal-regulating kinase 1 (ASK1)/JNK and TRB3 pathways, whose overexpression can induce a chronic ER stress state. 81

DNA methylation is an important epigenetic mechanism that regulates gene expression. 82 Abnormal DNA methylation patterns may lead to the downregulation of gene expression associated with ER function, which in turn affects the folding ability of the ER. 83 Histone modifications also regulate gene expression associated with ER stress. 84 The altered modification status of histones may affect the structure of chromatin and thus the transcription of ER stress-related genes. 85 In addition, epigenetic factors can interact with environmental factors to further exacerbate ER stress. For example, environmental factors such as diet, toxin exposure, and infections may alter the ER stress status by influencing epigenetic modifications such as DNA methylation and histone modifications. 86 In summary, genetic and epigenetic factors not only determine the ability of cells to respond to ER stress but also play important roles in the cellular response to environmental stress.

Dysfunction of mitochondria

Mitochondria are the energy factories of cells and are responsible for ATP production. 87 It plays an important role in the regulation of apoptosis, calcium ion homeostasis, and oxidative stress, and interacts with the ER through signaling pathways and substance exchange. 88 Numerous studies have shown that mitochondrial dysfunction can significantly increase the risk of ER stress in several ways. First, mitochondrial dysfunction directly reduces ATP production, an important energy source for the ER to maintain normal function. 89 Insufficient energy leads to impaired protein-folding processes in the ER, contributing to the accumulation of unfolded proteins. Second, the overproduction of ROS in mitochondria directly damages the ER membrane. 90 In addition, ROS affect folding enzymes and chaperone proteins (e.g., BiP) in the ER, thereby interfering with the normal folding process of proteins and leading to the accumulation of unfolded proteins, which triggers the ER stress response. 59 Third, when calcium ion release and storage are abnormal during mitochondrial dysfunction, resulting in altered calcium ion concentrations in the ER, excess calcium ions can cause ER stress. 91 This is because the ER also depends on normal levels of calcium ions to maintain its function, as mentioned in the previous sections. Finally, decreased mitochondrial function may also lead to changes in intracellular metabolites, and the inability to utilize these metabolic intermediates efficiently affects protein folding and modification within the ER, leading to the accumulation of unfolded or misfolded proteins. 92 If mitochondrial dysfunction and ER stress persist, cells may enter an apoptotic program, further affecting cell and tissue function. 93

Lack of oxygen

In addition to genetic alterations in cancer cells that can contribute to ER stress, abnormal conditions in the tumor microenvironment (TME) can also lead to sustained activation of the UPR pathway. 50 The Warburg effect suggests that cancer cells favor aerobic glycolysis, but normal cells rely primarily on anaerobic glycolysis to produce ATP. 94 Owing to rapid cell division and abnormal angiogenesis, hypoxic features arise in the tumor, thus disturbing the balance of the ER. 95 Research indicates that hypoxia, which is prevalent in tumors, increases both the level and activity of hypoxia-inducible factor-1α (HIF-1α), thereby inducing ER stress that can lead to irreversible cellular damage. 96

Nutrient availability

Cellular energy is supplied by the metabolism of glucose and lipids. 97 If the supply of nutrients is insufficient, the metabolic activity of the cells is limited, resulting in an energy deficit that interferes with the normal functioning of the ER. 98 A study investigating the gene expression profile of melanoma cells revealed a significant increase in isocitrate dehydrogenase 1 (IDH1), which is essential for cellular metabolism and energy conversion, 99 in response to ER stress. Compared with the standard energy requirements of cells, an inadequate supply of nutrients characterizes metabolic stress, which can quickly destroy ER homeostasis. Nutrient deprivation, which notably reduces glucose flux through the hexosamine pathway, curtails the metabolic intermediates necessary for the hexosamine biosynthetic pathway (HBP), thereby allowing activated ER stress to dictate the fate of malignant cells. 100 Glucose restriction also impairs mitochondrial ATP production, and energy deficiency affects the ability to fold proteins in the ER. 101 Moreover, fatty acids are not only a source of energy but also a building block of cell membranes. 102 In nutritional deficiency, the supply of fatty acids is also affected, which in turn affects the membrane structure and function of the ER, leading to ER stress. 103

Acidic pH

Studies have shown that ER stress is closely related to the pH of the intracellular environment. Changes in pH may lead to alterations in the permeability of cell membranes, causing changes in the exchange of ions and molecules inside and outside the cell, especially when acidosis conditions occur. 104 Cancer cells use aerobic glycolysis as a central metabolic pathway, producing lactate, which lowers the local extracellular pH. 105 After secretion, lactic acid destabilizes the HIF-1α protein and synergizes with hypoxia to robustly activate the ER stress response. 106 Recent studies have shown that lactate can also activate Caspase-12 to induce apoptosis and lung fibrosis in alveolar epithelial cells via the ATF4/CHOP axis during ER stress. 107 Sharma et al. verified that an acidic environment activates ER stress by detecting the splicing of XBP1 mRNA. 108 In addition, acidic pH activates ER stress-related pathways, leading to increased expression of IRE1, ATF6, and eIF2α. 109 IRE1 is activated by autophosphorylation of its intracellular kinase domain, leading to the dissociation of IRE1 from the dimer and the formation of the active form. 110 The acidic environment causes ATF6 to detach from the ER membrane, undergo Golgi processing, and be cleaved into the active transcription factor ATF6p50, which is subsequently translocated into the nucleus to initiate the transcription of a range of genes, including those involved in aspects of protein folding and lipid synthesis. 111 In addition, PERK under acidic stress activates the phosphorylation of eIF2α, which inhibits global protein synthesis and reduces the burden of new protein synthesis. 112

Oxidative stress

Oxidative stress is an imbalance between oxidation and antioxidant effects in the body, leading to the overproduction of oxidizing substances and dysfunction of the antioxidant defense system. 113 This state can cause inflammatory neutrophil infiltration, increased protease secretion, and the generation of oxidative intermediates. Furthermore, oxidative stress can initiate ER stress through various pathways. Products of oxidative stress have oxidative properties that can directly oxidize and damage protein structures within the cell. 114 Oxidatively damaged proteins usually lose their normal folded state, leading to aggregation and instability, accumulation in the ER, and triggering ER stress. 115 Notably, recent studies highlight the critical role of the Keap1/Nrf2 axis in bridging oxidative stress and ER homeostasis. For example, TRIM25, a ubiquitin E3 ligase induced during ER stress, promotes Nrf2 activation by ubiquitinating and degrading Keap1. This enhances antioxidant defenses (e.g., HO1 and NQO1), reduces ROS accumulation, and alleviates ER stress-induced protein misfolding. 116 Additionally, oxidative stress can precipitate ER stress by inhibiting protein-folding enzymes, impairing the function of molecular chaperones, or diminishing the efficiency of protein repair processes. 117 Under oxidative stress conditions, ROS and oxidative protein modifiers can directly or indirectly activate ER stress sensors, such as ATF6. The activation of these sensors triggers a cascade of ER stress signals, thereby inducing a series of adaptive responses. Jin et al. elucidated the dual role of ATF6 in ER stress and oxidative stress, which means that the hydroxylase produced by ATF6-induced oxidative stress can also act as an ER stress response element. 118

Therapy status

Radiotherapy induces ER stress, and the induction of ER stress responses may contribute to adaptive survival signaling in cancer cells. Since radiation-exposed cells exhibit increased UPR activity, several studies have shown that the knockdown of ER stress-related genes contributes to increased radiation-induced cell death. 119 During chemotherapy, various anticancer drugs induce robust ER stress responses, correct uncontrolled protein states, and determine the future of cells. Therapeutic regimens that rely on immune cell death (ICD) inducers, including cetuximab, anthracyclines, and oxaliplatin, 120 can trigger ER stress by depleting calcium ions within the ER, suggesting that genes associated with this mechanism could be drug targets and ultimately activate antitumor responses. 121 In addition, paclitaxel induces ER stress in breast cancer cells, which promotes the association of ring-finger protein 5 (RNF5), ubiquitination, and degradation of solute carrier transporter 1A5 (SLC1A5) and SLC38A2, and can promote anticancer drug efficacy. 122 Thus, depending on the setting and tumor type, the interplay between various anticancer drugs and ER stress signaling critically influences the endogenous anticancer immune response, markedly altering disease progression. 50 In addition, the ROS produced by the latest photodynamic therapy can also trigger protein misfolding, leading to ER stress. 123 For example, the fluorophore IR-34 can accurately trigger the ER stress response in tumor cells to stop cancer progression. Currently, novel nanomedicines have been developed to induce ER stress in tumor cells, and they exacerbate apoptosis by upregulating ER stress-associated proteins.

Downstream effectors of ER stress

In addition to the three classical pathways of the UPR, ER stress involves other downstream effectors for protein folding, transport, and degradation regulation, as well as many adaptive mechanisms for maintaining cellular homeostasis (Fig. 3 ). Fig. 3 Downstream effectors and multilevel regulation of ER stress. The goal of the UPR is to restore the normal function of the ER through several mechanisms: enhancement of protein folding and repair function, enhancement of protein degradation, and inhibition of protein synthesis. The cytoplasmic portion of IRE1 binds to TRAF2, which activates JNK and is involved in the regulation of apoptosis. IRE1 activation promotes the expression of the ERAD-related genes SEL1L and HRD1, which facilitate the degradation of unfolded or misfolded proteins via ERAD. Upon activation of ATF6, SEL1L also induces EDEM, which helps cells recognize and degrade unfolded or misfolded proteins. ATF6 promotes protein quality control mechanisms under ER stress by upregulating EDEM expression. In addition, TXNDC5 can be induced by ATF6, thereby increasing the efficiency of protein folding in the ER. PERK can regulate the expression of ERDJ4 by activating ATF4, which helps improve ER protein folding. In addition, the PERK signaling pathway upregulates Nrf2 via ATF4 and promotes antioxidant gene expression. PERK can also affect cell growth and autophagy through the mTOR signaling pathway. The activation of PERK inhibits mTOR, leading to alterations in cellular metabolism and the enhancement of autophagy processes, which can help remove damaged cellular components. Upon triggering of the UPR, the IRE1, ATF6, and PERK pathways are activated as downstream execution mechanisms, altering cellular features through different molecular and biochemical pathways. These features include proliferation, angiogenesis, metastasis, reactivation of dormant cells, cell death, cell metabolism, and therapeutic resistance

Downstream regulators of IRE1

IRE1, upon activation, promotes the expression of genes related to ERAD, including suppressor/enhancer of Lin-12-like (SEL1L) and 3-hydroxy-3-methylglutaryl reductase degradation (HRD1), which is a pathway responsible for recognizing and degrading unfolded or misfolded proteins in the ER. 124 For proteins that do not fold correctly, cells mark them for degradation via ERAD, preventing them from accumulating and causing cytotoxicity. 125 By degrading misfolded proteins, IRE1 helps maintain ER homeostasis. Furthermore, the cytoplasmic portion of IRE1 binds to TNF receptor-associated factor 2 (TRAF2), an articulatory protein that binds plasma membrane receptors to activate JNK. 126 Sustained activation of IRE1 can induce JNK through the TRAF2 pathway, which is involved in regulating cell survival and apoptosis, especially in the presence of more severe ER stress. On this basis, IRE1 can also promote activator protein 1 (AP1) activation through JNK. 127 AP1 is a transcription factor complex involved in regulating the expression of various genes. It plays an important role in mainly cell survival and apoptosis, which has been demonstrated in human aortic endothelial cells. 128 IRE1 also promotes the expression of interleukin-6 (IL-6), which acts as a proinflammatory cytokine that is associated with a variety of diseases (e.g., cancer and diabetes) by activating the JNK pathway to potentiate inflammatory responses. 129 Under severe ER stress, IRE1 induces the expression of FAS (CD95) and other proapoptotic factors and enhances apoptotic signaling. 130

Downstream regulators of ATF6

The activation of ATF6 induces ER degradation-enhancing α-mannosidase-like protein (EDEM) in the ERAD pathway to help recognize and degrade unfolded or misfolded proteins. 131 ATF6 promotes protein quality control mechanisms under ER stress by upregulating EDEM expression. 132 Gan et al. reported that EDEM3 overexpression attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma adiponectin levels. 133 Another ERAD-related gene, SEL1L, is involved in recognizing and removing misfolded proteins. Together with HRD1, it forms a complex responsible for delivering incorrectly folded proteins to the proteasome for degradation. 134 ATF6 enhances the ERAD pathway by activating SEL1L, ensuring that misfolded proteins are rapidly recognized and degraded, preventing these proteins from accumulating and triggering toxicity. 135 Homocysteine-induced ER protein (HERP), which is also involved in the ERAD pathway, can accelerate the degradation of misfolded proteins during ER stress via ATF6. 136 Protein disulfide isomerase (PDI) is an important ER enzyme responsible for forming and rearranging disulfide bonds in proteins to ensure correct protein folding. 137 Thioredoxin domain containing 5 (TXNDC5), a PDI, was recently shown to be induced by ATF6, increasing the efficiency of protein folding in the ER and potentially ameliorating liver fibrosis. 138 In addition, ATF6 can regulate cell survival in response to cellular stress and inflammation by affecting the expression of CCAAT/enhancer-binding protein (C/EBP). 139

Downstream regulators of PERK

PERK can regulate the expression of ER dnaJ 4 (ERDJ4) through ATF4, which acts as a chaperone protein to help improve the protein-folding ability of the ER and alleviate ER stress. 140 Growth arrest and DNA damage-inducible protein 34 (GADD34), one of the target genes of ATF4, can restore protein synthesis by promoting eIF2α dephosphorylation. 141 NADPH oxidase 4 (NOX4) plays a role in the cellular response to oxidative stress, and the PERK signaling pathway can regulate NOX4 expression to activate cellular autophagy events. 142 The PERK signaling pathway promotes antioxidant gene expression by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) through ATF4. 143 Mohamed et al. reported that tumor myeloid-derived suppressor cells (MDSCs) lacking PERK exhibited disrupted Nrf2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. 144 Therefore, Nrf2 activation protects cells from oxidative stress-induced damage, thereby preserving cell survival. In addition, C/EBPβ is activated in response to ER stress through the PERK pathway and is involved in regulating cell growth and survival. The activation of C/EBPβ can influence the cell cycle and apoptosis and has recently been shown to be effective in blocking MDSC activation in tumors, leading to TME remodeling and tumor regression. 145 Caspases are also key enzymes involved in apoptosis, and activation of the PERK pathway can direct the activation of executing enzymes, such as caspase-3, to trigger apoptosis. 146 PERK can also affect cell growth and autophagy by regulating the mechanistic target of the rapamycin kinase (mTOR) signaling pathway. 147 Under ER stress, the activation of PERK inhibits mTOR, leading to alterations in cellular metabolism and the enhancement of autophagy processes, which can help remove damaged cellular components and play a protective role in response to ER stress.

In summary, downstream regulators of ER stress help cells cope with ER dysfunction by participating in protein folding, transport, and degradation, as well as cellular homeostatic and adaptive mechanisms. These mechanisms are essential for maintaining cellular health and can effectively prevent cellular damage and diseases caused by abnormal protein folding.

Multilevel regulation of ER stress

Once the UPR is triggered, the IRE1, ATF6, and PERK pathways are activated as downstream executive mechanisms, altering cellular features through different molecular and biochemical pathways. 148 These features include proliferation, angiogenesis, metastasis, reactivation of dormant cells, cell death, cell metabolism, and treatment resistance (Fig. 3 ).

Proliferation

Since tumor cells typically reside in a highly metabolically active and fast-growing environment, an increased ER burden can trigger ER stress. Specifically, ER stress promotes tumor cell proliferation when signaling molecules in the ER stress pathway, such as XBP1, are activated, along with the expression of antioxidant response genes. 149 Additionally, a study demonstrated that persulfate-based degradation of perfluorooctanoic acid (PFOA) induced ER stress, activating the ROS-dependent ERK signaling pathway. 150 Low concentrations of PFOA induced ER stress and activated the PERK/eIF2α pathway in the UPR while significantly increasing ROS production. ROS further regulates kinase phosphorylation through the activation of extracellular signals, thereby promoting trophoblast cell proliferation. Furthermore, Blazanin et al. reported that Ras carcinogen-induced proliferation is directly related to ER stress, with the IRE1/XBP1 pathway playing a dominant role. 151 Consequently, these mechanisms enable tumor cells to adapt to stress, survive, and proliferate. In atherosclerosis, ER stress can contribute to the proliferation of vascular smooth muscle cells, leading to intimal thickening. 152 Zhou et al. reported that this effect is due mainly to increased CHOP expression, which in turn promotes cell proliferation by downregulating KLF4.

Angiogenesis

Angiogenesis, which is crucial for tumor growth, relies on intracellular ER stress signals to secure oxygen and nutrients, facilitating growth and waste removal. 50 It has been shown that activating IRE1 and PERK in tumor cells induces the expression of vascular endothelial growth factor (VEGF). Specifically, in glioblastoma, inhibiting IRE1 leads to the downregulation of various VEGFs, adversely affecting angiogenesis. 153 Insufficient expression of IRE1 has been linked to reduced angiogenesis and decreased growth rates, highlighting its role as a key regulator of tumor neovascularization and aggressiveness. Moreover, ER stress further promoted VEGF expression by activating the HIF-1α pathway. 154 Under a hypoxic environment, HIF-1α can promote neovascularization through the VEGF pathway, and ER stress enhances this process through IRE1, PERK, and other pathways. 155 The PERK/ATF4 arm of the UPR has been identified as a mediator of the angiogenic switch, with the inhibition of UPR signaling significantly reducing tumor growth and vascular density, suggesting a potential target for cancer therapy. 156 Unlike the traditional ER stress response, VEGF activates the UPR through phospholipase C‒gamma (PLCγ)-mediated interaction with the mTORC1 complex, where a lack of ATF6 or eIF2α significantly reduces VEGF-induced angiogenesis. 157

Metastatic

The UPR supports multiple stages of metastasis, especially through PERK’s role in upregulating lysosome-associated membrane protein 3 (LAMP3), which is essential for hypoxia-driven nodal metastasis, thereby amplifying metastatic traits. 158 Additionally, RNA editing proteins trigger ER stress in colorectal cancer metastasis, enabling ATF6, XBP1, and ATF4 to move to the nucleus, activate metastasis-related genes, and enhance tumor cell invasion. 159 In osteosarcoma cells, increased ATF6α cleavage and activity lead to increased BiP expression and an increased likelihood of metastasis. 160 Deletion of tumor suppressor candidate 3 (TUSC3) through miR-224/-520c enhances the ATF6α-dependent UPR and inhibits the p53-NM23H1/2 pathway, increasing the metastatic potential of lung cancer. 161 Elevated heat shock protein 47 (HSP47) levels enhance actin filament contractility via the interaction of IRE1 with nonmyosin, promoting metastasis in aggressive breast cancer cells. 162

Reactivation of dormant cells

Dormant cells, which remain hidden and asymptomatic for extended periods, can reactivate, significantly contributing to cancer recurrence after treatment and potentially serving as a stage for metastasis. 163 For example, cancer stem cells in tumors are often dormant and can enter a proliferative state through the reactivation of ER stress signals to drive tumor growth. 164 Studies have demonstrated that the activation of various UPR pathways, such as increased phosphorylation of PERK/eIF2α, supports dormant tumor cell survival. Inhibiting PERK signaling can reverse this phenotype, significantly improving treatment outcomes. 165 The three UPR pathways collectively contribute to the angiogenic, metastatic, and dormant properties of tumor cells, each to varying degrees.

Cell death

Cells initiate apoptosis if the ER stress response fails to maintain proteostasis, leading to persistent imbalance. 3 The apoptotic program is often attributed to dysregulated calcium homeostasis, with the ER playing a crucial role in calcium ion storage. 166 Following ER stress, stimulation from various signals, including PERK and eIF2α, opens inositol 1,4,5-triphosphate receptor (IP3R) channels in the ER membrane, causing a substantial release of calcium ions. 167 Elevated levels of calcium ions activate calpain by binding to calcium-dependent proteases. This enzyme cleaves various proteins, including B-cell lymphoma-extralarge (Bcl-xL), shifting it from being antiapoptotic to being proapoptotic. 168 Furthermore, activated calpain can move to the ER, where it cleaves and activates caspase-12 at multiple sites, playing a critical role in apoptosis. Additionally, triggering pharmacological ER stress selectively removes live sequestration of damaged ER and may help cells maintain a new steady-state level of ER abundance. 169 Chlorpromazine (CPZ), a novel pharmacological approach for treating glioblastoma, targets the ER and thus affects the UPR. This perturbation leads to a solid autophagic response that hinders the malignant features of glioblastoma. 170 ER stress exerts a direct antitumor effect on human colon cancer as an upstream regulator of lentinan (SLNT, with significant tumor growth inhibition), which increases the Ca2+ concentration, autophagy, and apoptosis. 171 In a recent study, high concentrations of PFOA resulted in ER stress overload that exceeded the compensatory capacity of the UPR, triggered sustained PERK/eIF2α activation, and upregulated the expression of the proapoptotic transcription factors ATF4 and CHOP. In contrast to low concentrations of PFOA, which promote cell proliferation, high concentrations of PFOA induce CHOP, thereby inhibiting the expression of the antiapoptotic protein BCL-2 and activating the apoptotic pathway. 150

Cellular metabolism

At the onset of ER stress, the activation of signaling pathways inhibits both glucose uptake and glycolytic processes. 172 Specifically, IRE1 activation inhibits translation and reduces glucose transporter type 4 (GLUT4) expression, decreasing glucose uptake and utilization. 173 In addition, activated PERK inhibits glucose uptake and utilization of external glucose by influencing the expression and activity of several key enzymes in the glycolytic pathway, decreasing the rate of fructose phosphate metabolism and thus inhibiting glucose metabolism. 174 ER stress-induced Ca2+ imbalance and UPR activation impair glucose metabolism, thereby promoting tumor progression. 175 ER stress also causes a decrease in the ability of the liver to respond to insulin by modulating the activity of enzymes in the liver associated with gluconeogenesis and glycogen synthesis. 176 Moreover, ER stress leads to impaired pancreatic β-cell function, affecting insulin synthesis and secretion, which in turn may trigger insulin resistance and diabetes. 177

In addition, the activation of ER stress affects lipid metabolism. ER stress inhibits adipocyte differentiation, such as by inhibiting beige adipogenesis through the PERK signaling pathway, which exacerbates metabolic dysfunction. Park et al. reported that estrogen can alleviate ER stress and restore the differentiation ability of adipose precursor cells through the NAMPT-NAD+ axis, providing a new target for the treatment of metabolic diseases such as obesity. 178 The PERK pathway in the UPR can promote SREBP processing and nuclear translocation by phosphorylating EIF2α, leading to INSIG1 degradation, which increases the expression of lipid synthesis-related genes. Sustained activation of SREBP1c promotes hepatic lipogenesis, leading to excessive cholesterol accumulation. 179 In addition, ER stress regulates INSIG stability through GP78, which affects SREBP activity and cholesterol synthesis. GP78 deficiency leads to SREBP1 hyperactivation and accelerates age-related metabolic disorders. 180 Lipid synthesis and ER stress are bidirectionally regulated. SREBP activation relieves short-term stress, but long-term SREBP activation increases the burden on the ER, resulting in a vicious cycle. 181 ER stress also inhibits the expression and activity of enzymes in the lipid synthesis pathway, leading to a decrease in intracellular triglyceride synthesis, which in turn leads to disturbed lipid metabolism. 182 ER stress sometimes contributes to lipid metabolism, and its activation enhances lipid degradation pathways, such as autophagy and lipoprotein metabolic pathways, which promote lipolytic metabolism. 183 Intervention with stearoyl coenzyme A desaturase inhibitors can effectively block tumor spread by altering lipid homeostasis and triggering ER stress. 184 In the regulation of energy metabolism, ER stress inhibits mitochondrial function and oxidative phosphorylation processes, thereby reducing intracellular ATP production, which is achieved mainly by regulating the signaling pathways of two key energy sensors, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 signaling affects tumor growth in patients with xenograft hepatocellular carcinoma.

Treatment resistance

Radiotherapy, a primary strategy for cancer treatment, sensitizes cells to stimuli, including ER stress. 185 On the one hand, ER stress can attenuate radiation-induced cytotoxic effects, leading to radioresistance. Sestrin2 normally aids in cancer therapy, but radiotherapy upregulates Sestrin2, mitigating oxidative and ER stress and thereby resisting treatment. 186 On the other hand, ER stress has also been reported to reduce radioresistance in a study of lung cancer. Baek et al. demonstrated that the interaction of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) with protein kinase C via IRE1 activates caspase-2,4-dependent apoptosis to reduce radioresistance in an ER stress-mediated manner. 187 The emergence of chemotherapeutic resistance, often linked to high mortality rates, highlights the critical roles of autophagy and apoptosis. Specific activation of one or more UPR pathways leads to different intensities and final targets of ER stress responses, which induce different chemoresistance mechanisms: enhancement or attenuation. A study on lung adenocarcinoma (LUAD) cells revealed that increasing cisplatin concentrations promote the ER stress-induced transition of the XBP1 3′UTR, reducing chemoresistance and enhancing therapeutic efficacy. 188 Wong et al. reported that stearoyl-CoA desaturase 1 (SCD1) promotes the formation of lipid droplets, which attenuates chemotherapy-induced ER stress. Therefore, pharmacological inhibition of SCD1 can increase the expression levels of eIF2α, ATF4, and CHOP to attenuate chemoresistance, an approach that has been clinically demonstrated. 189 Tunicamycin significantly increased chemotherapy-induced death in gastric cancer cells by inducing ER stress, primarily through the upregulation of PERK, IRE1, and XBP1. 190

Moreover, ER stress has the negative effect of enhancing chemoresistance during the treatment of some cancers. ER stress-induced silencing of PHLPP made cancer cells resistant to chemotherapeutic drugs in a study by Guo et al. 191 The knockdown of PHLPP can increase the expression of autophagy-related genes downstream of the eIF2α/ATF4 signaling pathway, one of the important pathways in the UPR, which can promote chemoresistance in colon cancer. A recent study revealed that high expression of LIM domain kinase 1 (LIMK1) in colorectal cancer cells promotes eIF2α phosphorylation, which induces ER stress and increases resistance to 5-fluorouracil (5-FU). 192 The mechanism underlying 5-FU chemoresistance involves LIMK1 interaction with eIF2α, which modulates the PERK/eIF2α/ATF4 axis to reduce 5-FU-induced apoptosis in tumor cells. In conclusion, ER stress-associated genes could be potential targets for circumventing chemoresistance.

Role of ER stress in diseases

ER stress is increasingly recognized as a critical player in the pathophysiology of various diseases. Emerging evidence links ER stress to a wide array of conditions, including cancers, cardiovascular disorders, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. Understanding the multifaceted roles of ER stress in these diseases may provide insights into novel treatment strategies, underscoring the importance of this cellular stress response in both health and disease.

Cancers

Tumorigenesis is a progressive process that involves a multistage response and the accumulation of mutations. 193 As this process progresses, cancer cells increasingly evade in vivo regulatory mechanisms, leading to the invasion of normal tissues and endowing mutant cells with new characteristics, including ER dysfunction. 194 ER stress plays a pivotal role in cancer biology, influencing tumor initiation, progression, and response to therapy. In the context of cancer, the UPR can have dual roles. On the one hand, it promotes cell survival and tumor growth by enhancing metabolic adaptation and resistance to apoptosis. On the other hand, prolonged ER stress can induce cell death, highlighting the delicate balance between survival and apoptosis that cancer cells exploit. Understanding the intricate relationship between ER stress and cancer pathophysiology is crucial for developing innovative therapeutic approaches to improve patient outcomes. We summarize recent studies on lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, glioblastoma, melanoma, ovarian cancer, and leukemia, including studies on the role of ER stress in tumors and immune cells in cancer (Table 1 ). Table 1 Effects of ER stress in solid tumors Cancer type Key ER stress pathways Key molecules/regulators Impact on the tumor Therapeutic targets/strategies Lung cancer IRE1/XBP1, PERK/ATF4, GRP78 GRP78, SLC7A11, CYB5R3, CHOP - GRP78 is linked to better prognosis. Targeting CYB5R3, SLC7A11 inhibition, and CHOP modulation. - CYB5R3 induces apoptosis via PERK/ATF4 and IRE1/JNK. - CHOP in MDSCs impairs T-cell responses. Gastric cancer PERK/ATF4, IRE1/XBP1, GRP78 SEC23A, SCNN1B, HAND1 - SEC23A promotes autophagy to evade apoptosis. Targeting SEC23A, SCNN1B activation, HAND1 overexpression. - SCNN1B triggers caspase-dependent apoptosis. - HAND1 induces ER stress via ROS. Colorectal cancer IRE1/XBP1, PERK/eIF2α, ATF4 XBP1, KLF16, DEH, GCS1 - XBP1 in TAMs promotes pro-tumor cytokines. XBP1 inhibition, DEH as a therapeutic agent, and KLF16 targeting. - DEH induces autophagy via PERK/IRE1. - GCS1 reduces ER stress-mediated apoptosis. Hepatocellular carcinoma IRE1/XBP1, ATF6, PERK/ATF4 SEC63, GPR109A, FGF19 - IRE1-phosphorylated SEC63 promotes metastasis. SEC63 inhibition, GPR109A blockade, ATF4 suppression (e.g., DSF/Cu). - GPR109A blockade enhances CD8 + T-cell response. - FGF19 counteracts ER stress via ATF4. Prostate cancer IRE1/XBP1, ATF6, PERK/ATF4 AR, DRP1, ACSS3, ATF6 - AR induces ER stress genes. ATF6 inhibitors, ACSS3 restoration, EPHB4 inhibition. - ACSS3 restoration increases ER stress-induced apoptosis. - ATF6 deletion inhibits metastasis. Breast cancer IRE1/XBP1, PERK/CHOP, METTL3/14 IRE1, METTL3, METTL14, σ2 receptor - IRE1 knockdown normalizes vasculature. IRE1 inhibitors, METTL3/14 targeting, σ2 receptor agonists (e.g., A011). - METTL3/14 enhance m6A methylation. - σ2 ligands induce PERK/CHOP apoptosis. Ovarian cancer IRE1/XBP1, PERK/ATF4, UPR in TME HOOK1, XBP1, TAGLN2, SCD - XBP1 in DCs disrupts antigen presentation. XBP1 inhibition in DCs, SCD targeting (e.g., lipid metabolism modulators), and Elaiophylin (autophagy inhibitor). - SCD knockdown induces apoptosis via IRE1/PERK. - TAGLN2 enhances CD8 + T-cell cytotoxicity. Glioma IRE1/XBP1, PERK/ATF4, GRP78 GRP78, UBE2D3, FKBP9, TRPV1 - GRP78 knockdown reduces chemoresistance. GRP78 inhibitors (e.g., temozolomide adjuvants), TRPV1 activation via NO release. - FKBP9 deletion activates IRE1/XBP1-induced apoptosis. - TRPV1 activation inhibits invasion. Melanoma IRE1/XBP1, PERK/CHOP TRAIL-R2, RIPK1, B7H6 - ER stress enhances BRAFi-induced apoptosis. RIPK1 inhibitors, PERK pathway blockade, and CO-induced ER stress modulation. - RIPK1 knockdown sensitizes cells to ER stress. - PERK inhibition enhances PD-1 efficacy.

Respiratory system

Lung cancer

In 2005, Uramoto et al. first studied the expression of GRP78 in human lung cancer and its clinical significance. 195 Lung cancer patients with positive GRP78 expression tended to have a better prognosis; therefore, the ER stress pathway mediated by GRP78 might be responsible for controlling the growth of lung cancer cells. Oncogenic KRAS is a major driver of lung cancer, and Hu’s team probed the mechanism involved in ER stress. 196 Inhibiting solute carrier family 7 member 11 (SLC7A11) increases the activation of IRE1, PERK, and GRP78 as well as the transcription of CHOP, ATF4, and ATF6. Intense oxidative stress and ER stress-mediated apoptosis are cytotoxic to KRAS-mutant tumors. Furthermore, Xu et al. reported that O-GlcNAc transferase (OGT) significantly enhances the growth, migration, and invasion of lung cancer cells, and its mechanism is inextricably linked to ER stress. 197 OGT induced palmitate production, which increased the protein expression of GRP78 and IRE1, leading to severe activation of the oncogenic pathways JNK/c-jun/AP1 and NF-κB. A new tumor suppressor, Cytochrome b5 reductase 3 (CYB5R3), which induces ER stress-mediated apoptosis in lung cancer cells through the PERK/ATF4 and IRE1/JNK pathways, was identified in 2024. 198 Metabolomic analysis revealed that the overexpression of CYB5R3 also increased nicotinamide adenine dinucleotide (NAD+) production, a process that activates ER-resident protein poly (ADP-ribose) polymerase 16 (PARP16), which similarly induces ER stress.

Digestive system

Gastric cancer

In 2009, Zhang et al. first reported the effects of ER stress on gastric cancer cells. 199 Inhibition of MEK blocked GRP78 upregulation and enhanced ER stress-induced apoptosis in gastric cancer cells through a caspase-dependent mitochondria-mediated mechanism. Recently, preprotein translocation factor (SEC62) was shown to be significantly upregulated in gastric cancer and to promote the migration and invasion of gastric cancer cells. 200 SEC62 activates autophagy by affecting PERK/ATF4 expression and UPR recovery, which promotes gastric cancer metastasis. In gastric cancer, ER stress promotes autophagy by increasing the transcript level of Sec23 homolog A (SEC23A), which in turn regulates the cellular localization of Annexin A2 (ANXA2). 201 ER stress, SEC23A, and autophagy form a negative feedback loop to maintain the survival advantage of gastric cancer cells from ER stress-induced apoptosis. Owing to the tumor cell protective function of SEC23A under ER stress, it may be a promising therapeutic target that is expected to limit the progression of gastric cancer. Moreover, Kuang et al. reported that ectopic expression of hand-and-neural-crest-derivative-expressed 1 (HAND1) can inhibit the growth and migration of gastric cancer cells. 202 Mechanistically, HAND1 expression increases ROS levels and the cytosolic calcium ion concentration, which further kills tumor cells through ER stress-mediated apoptosis.

Colorectal cancer

In 2006, Guichard et al. applied ER stress for the first time in the treatment of colorectal cancer, and they reported that dihydroxyphenylethanol (DEH) induced apoptosis in colorectal cancer cells by promoting both branches of IRE1/XBP1/GRP78 and PERK/eIF2α. 203 For the first time, the anticancer effects of DEH on colorectal cancer and its mechanism were investigated by Li et al. 204 Experiments revealed that DEH induced ER stress by activating the PERK/eIF2α and IRE1/XBP1 pathways, which stimulated autophagy in tumor cells, suggesting that DEH may be a potential anticolorectal cancer drug. In studying the effects of metabolic pathways on colorectal cancer, Lin’s team noted that tumor tissues have higher levels of cysteine, which may result from the upregulation of genes encoding cysteine transporters (SLC1A4, SLC1A5) regulated by ROS and ER stress through the transcription factor ATF4. 205 Recently, Chen et al. investigated a pathway that affects colorectal cancer cell survival and apoptosis decisions and experimentally confirmed that glucosidase I (GCS1) expression is significantly upregulated in colorectal cancer. 206 GCS1 functions to bind GRP78 and promote its degradation, which also leads to reduced ER stress-mediated apoptosis in colorectal cancer cells and promotes colorectal cancer progression.

Hepatocellular carcinoma

As early as 2003, Shuda’s team revealed the involvement of the ER stress pathway genes ATF6, XBP1, and GRP78 in hepatocellular carcinoma. 207 Recent studies have indicated that SEC63 is a new regulator of metabolism in hepatocellular carcinoma cells. 208 When ER stress occurs, the IRE1 pathway phosphorylates SEC63 at T537, thereby activating SEC63, which functions to promote metastasis in hepatocellular carcinoma cells. Furthermore, the ATF6 pathway often acts in conjunction with IRE1. An early study revealed that in macrophages, oxidized low-density lipoprotein (ox-LDL) causes the upregulation of scavenger receptor cluster of differentiation 36 (CD36), which leads to the upregulation of IRE1 and the induction of the nuclear translocation of ATF6, thereby activating ER stress. 209 In addition, Teng and colleagues reported that FGF19 protects hepatocellular carcinoma cells from ER stress, mainly through the ability of ATF4 to directly bind to the FGF19 promoter and thus counteract the stress response. 210 Recently, He et al. reported that during ER stress-driven hepatocellular carcinoma progression, HMMR derived from CHOP transcription alleviates ER stress by promoting autophagy-lysosomal activity, which could play a role in controlling the progression of hepatocellular carcinoma. 211

Genitourinary system

Prostate cancer

In 2004, GRP78 was first revealed to be a functional molecular target for identifying prostate cancer patients for clinical application. 212 Furthermore, in prostate cancer, c-MYC is one of the highly activated oncogenic pathways and is closely related to UPR pathway genes. 38 IRE1/XBP1 pathway activity is required for the c-MYC signaling pathway, which in turn promotes prostate cancer progression. In a subsequent study, acyl-CoA synthetase short-chain family member 3 (ACSS3) was found to be downregulated and was associated with poor prognosis. 213 Zhou et al. reported that restoring ACSS3 expression in prostate cancer cells significantly increased ER stress-induced apoptosis, in which the expression of CHOP, PERK, ATF6, and XBP1 was significantly increased. Pachikov’s team confirmed that ATF6 is a new promising target for prostate cancer therapy. 214 Through ethanol stimulation, S1P and S2P in the Golgi apparatus of prostate cancer cells are translocated to the ER, leading to ATF6 cleavage, thereby activating ER stress. Mouse experiments revealed that ATF6 deletion significantly retarded the growth and metastasis of prostate tumor cells. Among other factors, the phosphorylation of eIF2α, a feature of ICD, promoted cell death in prostate cancer cells, suggesting a potential role for EPHB4 inhibition in immunotherapy. Blomme’s team reported that 2,4-dienoyl-CoA reductase (DECR1) deletion decreases prostate tumor cell growth via a mechanism in which DECR1 disrupts the balance between saturated and unsaturated phospholipids, leading to ER stress. 215 This process increases the sensitivity of prostate tumor cells to iron death, leading to the inhibition of tumor growth.

Breast cancer

In 2004, the expression of VEGF and IL-8 in human breast cancer was reported to be sensitive to ER stress, which affects mainly the upregulation of GRP78 expression. 216 Metabolic analysis of breast cancer cells revealed that GRP78 expression increased the intracellular linoleic acid concentration, and its inhibition increased macrophage infiltration, thereby reducing breast tumor growth. 217 Harnoss’ team reported that IRE1 knockdown significantly reversed ER stress adaptation in breast cancer cells, which led to normalization of the tumor vasculature and slowed breast cancer progression. 218 Moreover, IRE1 disruption also led to remodeling of the TME, reducing the number of cancer-associated fibroblasts and myeloid-derived suppressor cells. In 2024, Wang’s team reported for the first time that ER stress can significantly increase the level of m6A methylation in breast cancer cells through XBP1-dependent upregulation of METTL3 and METTL14 transcription. 219 This process enhances the stability of ER phagocytosis regulator mRNAs, thereby increasing the degree of phagocytosis, which demonstrates that METTL3 and METTL14 may be potential therapeutic targets for breast cancer. Additionally, activated human epidermal growth factor receptor 2 (HER2) can also be sensitized to apoptosis under ER stress via a PERK/ATF4/CHOP-dependent pathway, which has important therapeutic value against breast tumor cells. 220

Ovarian cancer

In 2006, Lei et al. reported for the first time that the activation of the ER stress response in ovarian cancer cells inhibited the proliferation of ovarian cancer cells by upregulating GRP78 via the use of 1,1-bis(3′-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu). 221 In a recent study, Carnero et al. identified a novel ovarian cancer therapeutic target, HOOK1. 222 As a result, UPR signaling was activated in HOOK1-downregulated tumor cells, causing an increase in ER stress and leading to cancer stem cell death. In a recent study, Zhao’s team used lipidomics and stimulated Raman scattering (SRS) microscopy to confirm that stearoyl CoA desaturase (SCD) knockdown leads to rapid activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 axes in the ER stress response. The XBP1 and PERK/eIF2α/ATF4 axes are involved in the ER stress response, which leads to apoptosis and tumor growth inhibition in ovarian cancer cells. 184 Additionally, Li et al. developed a novel autophagy inhibitor, Elaiophylin, which induces apoptosis in ovarian cancer cells by triggering excessive ER stress through overactivation of the MAPK pathway. 223 The results of gene set enrichment analysis (GSEA) revealed that elaiophylin was able to activate ER stress by increasing the protein levels of ATF4 and CHOP.

Blood and lymphatic system

Leukemia

B cells are the main component of humoral immunity and are the most extensively studied cells in leukemia or lymphoma. In 2010, ER stress was shown to be a novel target for the treatment of chronic lymphocytic leukemia (CLL) by Rosati et al. Downregulation of ER signaling by siRNA with BiP/GRP78 increased apoptosis in CLL cells. 224 Tang et al. established a mouse model of CLL that lacks XBP1 in B cells to explore how ER stress regulation affects disease progression. 35 XBP1 deficiency resulted in significantly slower leukemia progression. In addition, researchers have developed a potent IRE1 RNase inhibitor called B-I09. Since the immune system of CLL patients may be unable to clear abnormal B cells effectively, B-I09 may inhibit disease progression by inducing B-apoptosis. This is likely because ER stress renders XBP1 critical for plasma cell differentiation and immunoglobulin secretion, making it an attractive therapeutic target. 225 In addition, Lamothe’s team investigated the mechanism by which carfilzomib induces CLL cell death, which is inextricably linked to ER stress. 226 Carfilzomib treatment resulted in elevated protein levels of ATF4 and CHOP, while the accumulation of CHOP increased the cytotoxicity to CLL cells, which contributed to increased CLL apoptosis.

In 2006, Yanamandra et al. validated for the first time the mechanism of action of tipifarnib and bortezomib in acute myeloid leukemia (AML), where enhanced activation of the ER stress response under conditions of fibronectin adhesion led to apoptosis in AML cells. 227 Touriol’s team studied the mechanism by which ER stress affects chemotherapy sensitivity. 228 Sustained activation of XBP1 expression in AML cells induces apoptosis. In contrast, moderate XBP1 expression enhances chemosensitivity, possibly because the genes downstream of XBP1, miR-22-3p or miR-22, significantly reduce cell viability. Furthermore, a recent study revealed that the XBP1/miR-22/SIRT1 axis plays a critical role in AML, its triggering of ER stress induces apoptosis in AML cells, and moderate XBP1 expression enhances chemosensitivity. 228

In 2009, Hernández-Espinosa’s team combined L-asparaginase (L-ASP) and dexamethasone for the treatment of acute lymphoblastic leukemia (ALL), which promoted the expression of GRP78, leading to an exacerbation of the UPR, and the use of this regimen reduced the risk of thrombosis. 229 Both animal and clinical trials have demonstrated that high expression levels of the UPR downstream effector XBP1 predict poor B-ALL prognosis. 230 In a recent study, the development of T-ALL induced strong activation of PERK in the myeloid endothelial vascular ecological niche, which in turn led to increased angiogenesis via PERK/eIF2a/ATF4 axis activation. 231 Liu et al. reported that specific deletion of PERK improved the number of bone marrow endothelial cells, promoted ALL apoptosis, and increased overall survival.

Nervous system

Glioma

In 2007, Pyrko et al. first identified the UPR regulator BiP/GRP78 as a new target for the treatment of glioma, and knocking down BiP/GRP78 reduced the resistance of tumor cells to temozolomide. 232 Obacz’s team reported that this may be because the IRE1/XBP1 pathway increases the expression of the ubiquitin-binding E2 enzyme (UBE2D3), which activates the NF-κB pathway and leads to bone marrow infiltration in glioma. 233 Recently, the downregulation of FK506-binding protein 9 (FKBP9) was shown to significantly inhibit the growth of glioma cells. 234 Deletion of FKBP9 activated the IRE1/XBP1 pathway, which enhanced the apoptotic process of tumor cells via ER stress. Li’s team also recently discovered an important indicator related to the development of glioma. SelK-induced downregulation of ER stress led to the upregulation of β-TrCP1 expression, which accelerated ubiquitin-dependent CDK4 degradation and ultimately impaired glioma cell growth. 235 A recent study revealed that the transient receptor potential vanilloid 1 (TRPV1) ion channel is overexpressed on the ER in glioma cells and that its activation can regulate ER stress and thus inhibit the invasion of glioma. 236 Li et al. successfully activated the TRPV1 ion channel via in situ release of nitric oxide (NO), leading to multimodal killing of tumor cells, which is an effective strategy to inhibit glioma.

Skin system

Melanoma

In 2007, Jiang et al. first used the ER stress inducer tunicamycin for the treatment of melanoma, which can sensitize melanoma cells to apoptosis by activating IRE1 and ATF6 and thus upregulating TRAIL-R2. 237 When melanoma cells are subjected to pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG), IRE1/XBP1 is activated and thus enhances heat shock factor protein 1 (HSF1) expression, leading to increased receptor (TNFRSF)-interacting protein kinase 1 (RIPK1) expression in melanoma cells. 238 RIPK1 enhances melanoma cell survival through the activation of autophagy, suggesting that the knockdown of RIPK1 may be a useful strategy to increase the sensitivity of melanoma cells to therapeutic agents that induce ER stress. Niessner’s team reported that BRAF inhibitors (BRAFis) induce ER stress, thereby amplifying their proapoptotic activity in melanoma, where BRAFis significantly activate the PERK/ATF4/CHOP pathway and phosphorylate eIF2α. 239

Tumor immunity

In lung cancer, studies have shown that ER stress is a key hub for tumor immunosuppression by regulating the function and survival of MDSCs. In particular, in tumor-infiltrating MDSCs, UPR activation is followed by elevated levels of CHOP, which is directly related to the ability of MDSCs to impair T-cell responses. 240 MDSCs maintain survival and enhance immunosuppression in the harsh tumor microenvironment through CHOP-dependent stress adaptation mechanisms. Inhibition of CHOP or upstream stress signals (e.g., ROS/PNT scavengers) may reverse the immunosuppressive function of MDSCs and enhance antitumor immunity. 241 CHOP-deficient MDSCs lose their immunosuppressive capacity due to decreased IL-6 secretion and reduced STAT3 activity, instead promoting antitumor T-cell responses and significantly delaying tumor growth. CHOP-deficient MDSCs exhibit reduced apoptosis but impaired function, suggesting that ER stress plays a key role in balancing MDSC survival and function (Fig. 4 ). Fig. 4 Role of ER stress in the tumor-immune microenvironment. The ER stress response plays a key role in the activation and functional maintenance of immune cells. CO-induced activation of PERK in CD8+ T cells improves the antitumor function of CD8+ T cells and enhances mitochondrial function. ROS cause ER stress via the PERK/CHOP pathway, leading mainly to an increased immune response in CD8+ T cells. Cholesterol enrichment in the TME properly activated the ER stress signaling pathway in CD8+ T cells, and XBP1 was significantly upregulated during this process, promoting the apoptosis of tumor cells. Effective inhibition of IRE1/XBP1 induces B-apoptosis to suppress leukemia progression. Excessive activation of the IRE1/XBP1 pathway in DCs impairs their antigen-presenting capacity, leading to diminished antitumor capacity of T cells. Inhibition of XBP1 expression in DCs restored their immune properties and enhanced the immunocompetence of CD8+ T cells. Excessive activation of the IRE1 and ATF6 signaling pathways in NK cells reduces their cytotoxicity. When either of these two major regulators is knocked down, cytotoxicity to tumor cells can be activated. Excessive IRE1 also directly regulates the c-MYC signaling pathway and mitochondrial respiration to inhibit NK cell proliferation. In addition, ER stress promotes the expression of the NK cell ligand B7H6 through proper activation of eIF2α phosphorylation via PERK signaling, thereby controlling tumor progression. In tumor-infiltrating MDSCs, excessive UPR activation is followed by elevated CHOP levels, which can promote MDSC apoptosis, leading to reduced tumor cell survival time. Excessive activation of either IRE1/XBP1 or GRP78 in TAMs inhibits macrophage phagocytosis, which drives cancer progression, whereas weakening of XBP1 enhances phagocytosis by tumor cells

RNA sequencing and immunofluorescence analysis revealed that the spliced form of XBP1 was significantly upregulated and positively correlated with the expression of ER stress markers (e.g., BIP and CHOP) in tumor-associated macrophages (TAMs) from colorectal cancer patients and mouse models. 242 This activation was not observed in normal tissue macrophages, suggesting that the tumor microenvironment is an important trigger for XBP1 activation. XBP1 directly binds and regulates the transcription of protumorigenic cytokines (e.g., IL-6, VEGFA, and IL-4). Knockdown of XBP1 significantly reduced the expression of these cytokines, thereby inhibiting tumor cell proliferation and metastasis. In addition, experiments revealed that the knockdown of XBP1 also reduced the expression of SIRPα and THBS1, which could significantly enhance the phagocytosis of TAMs and disrupt the immune escape of tumor cells. Analysis of clinical data revealed that TAMs with high XBP1 expression were closely associated with poorer survival in colorectal cancer patients. Therefore, targeting XBP1 signaling in TAMs may be a potential strategy for colorectal cancer therapy. A study by Márquez et al. revealed that stimulation of dendritic cells (DCs) by pathogen-associated molecular patterns activates not only IRE1 signaling but also, to a lesser extent, the PERK signaling pathway. 243 In addition, ER stress induces DCs to produce IL-23, which has been proven to be a major driver of colorectal cancer cell growth. 244 Inhibition of IRE1α nucleic acid endonuclease activity or PERK reduces IL-23 production and may be a new direction for the treatment of colorectal cancer or other IL-23-dependent inflammatory diseases.

To improve the immunotherapeutic efficacy against hepatocellular carcinoma, Yang and her team reported that blocking GPR109A in tumors triggers antitumor responses in CD8+ T cells. 245 Myeloid cells compete with tumor cells for glutamine uptake, disrupting myeloid ER homeostasis and promoting GPR109A expression via the IRE1/XBP1 pathway. If the IRE1/XBP1 signaling pathway is inhibited or glutamine is supplemented, the immunosuppressive effect of GPR109A can be eliminated, suggesting that GPR109A may be a potential drug target for treating hepatocellular carcinoma. Furthermore, IRE1 is involved in the cytotoxicity of natural killer (NK) cells together with ATF6. 246 Knocking down IRE1 and ATF6 in hepatocellular carcinoma cells significantly increased their sensitivity to NK cell-mediated killing. During UPR activation, the IRE1 and ATF6 signaling pathways decrease the sensitivity of NK cells to cytotoxicity. This decrease in sensitivity is due to the indirect effects of the ATF6 and IRE1 signaling pathways on the expression of the NK cell receptor CD226. When knocked down, either of these two master regulators can activate cytotoxicity in hepatocellular carcinoma cells. 247

In breast cancer, Wen et al. reported that 6-epi-ophiobolin G (MHO7) can induce immunogenic cell death through the CHOP pathway during ER stress. The upregulation of MHO7 triggers ROS, which leads to ER stress through the PERK/CHOP pathway, leading mainly to an increase in CD8+ T-cell immune responses. 248 Additionally, MHO7 triggers oxidative stress through ROS generation and glutathione depletion, further exacerbating ER stress. This leads to elevated cytoplasmic Ca ion levels, thereby collapsing the mitochondrial membrane potential and promoting apoptosis. 249 Knockdown of CHOP partially reversed MHO7-induced Bax expression and Caspase-3 activation, a process that enhances tumor immunogenicity and induces a strong immune response. In a mouse model, MHO7-pretreated tumor cells induced long-term immune memory, inhibited secondary tumor formation, and significantly prolonged mouse survival.

In ovarian cancer, recent discoveries indicate that prolonged activation of the IRE1/XBP1 pathway in some DCs within the TME upregulates various UPR factors and induces lipid accumulation, weakening their antigen-presenting ability. 250 Ovarian tumor-infiltrated DCs exhibit marked upregulation of the expression of UPR factors, including BiP and CHOP, along with potent XBP1 activation. This process, in turn, disrupts the antigen-presenting ability of DCs, thereby weakening the antitumor capacity of T cells. 251 Inhibition of the ER stress response reduces T-cell depletion and improves T-cell antitumor function in the TME. Experiments have shown that tumor-associated DCs lacking XBP1 display significant downregulation of multiple genes involved in triglyceride biosynthesis. The activation of XBP1 leads to aberrant lipid accumulation, which in turn inhibits the ability of tumor-associated DCs to support antitumor T cells, thereby driving ovarian cancer progression. Environmentally induced activation of the IRE1/XBP1 signaling pathway in ovarian cancer limits glutamine abundance, inhibiting CD4+ T-cell mitochondrial respiration. 252 Animal experiments revealed that mice deficient in XBP1 exhibited delayed tumor progression and improved survival. Therefore, controlling targeted IRE1/XBP1 signaling in CD4+ T cells may help to restore the metabolic capacity and antitumor ability of T cells from ovarian cancer patients.

In leukemia, IRE1 and XBP1 act as upstream regulators that directly regulate the c-MYC signaling pathway and mitochondrial respiration to control the proliferation of NK cells. The oncogene MYC can activate the UPR of NK cells in multiple ways, affecting ALL cell survival by influencing cell growth, protein synthesis, and cell metabolism. 253 , 254 This landmark study was the first to identify c-MYC as a novel, direct downstream target of XBP1 in the regulation of NK cell proliferation. That same year, it was reported that extracellular vesicles from NK cells could induce ER stress in ALL cells, mediating cell death. 255 NK cell-derived extracellular vesicles activate the UPR by altering the expression of the ER chaperone proteins BiP and Ero1-Lα, ultimately triggering the apoptosis or necrosis of tumor cells. However, these experiments did not identify the key ER stress-related genes involved, highlighting the need for more in-depth mechanistic studies in the future.

A recent study by De Leo et al. revealed that in the glioma TME, monocyte-derived macrophages (MDMs) play a key immunosuppressive role through ER stress-mediated metabolic reprogramming, the molecular mechanism of which is closely linked to the PERK signaling pathway. 256 Hypoxia and nutrient deprivation signaling in the glioma microenvironment activate the ER stress sensor PERK, whose downstream transcription factor ATF4 directly upregulates the expression of GLUT1 to increase glucose uptake and glycolysis in MDMs. PERK-driven glucose metabolism not only provides energy for MDMs but also remodels the epigenetic landscape and maintains their immunosuppressive phenotype through lactic acid production and histone lactylation. The inhibition of PERK expression in MDMs prevents histone acetylation, leading to the accumulation of T cells in glioma and the retardation of tumor growth. Knocking down PERK was found to significantly reduce GLUT1 expression and lactate levels, decrease IL-10 secretion, and restore CD8+ T-cell infiltration and function within tumors in MDMs in mouse experiments.

Previous melanoma studies have shown that cholesterol enrichment in the TME activates the ER stress signaling pathway in CD8+ T cells. 257 Notably, XBP1, a key ER stress response pathway member, is significantly upregulated during this process. Furthermore, Raines et al. reported that IL-4 increases PERK expression in macrophages within melanoma, promoting the activation of immunosuppressive M2 macrophages. 258 Consequently, inhibition of the PERK pathway in ER stress suppresses the immunosuppressive activity of macrophages and may increase the efficacy of programmed cell death 1 (PD-1) inhibitors. Furthermore, a controlled variable experiment revealed that ER stress promotes the expression of the NK cell ligand B7H6 through the PERK signaling pathway. 259 B7H6 depends on PERK activation of eIF2α phosphorylation to regulate its expression levels and thus control melanoma progression. A recent study revealed that carbon monoxide (CO)-induced ER stress alters mitochondrial function in CD8+ T cells. 260 Specifically, CO-induced transient PERK activation in CD8+ T cells significantly improves their control over melanoma and enhances mitochondrial function. This research offers a novel approach to cancer treatment modalities that target ER stress, highlighting the delicate balance between ER stress sensor activation and the regulation of cellular antitumor capacity. In summary, activation of the PERK signaling pathway in tumor cells impairs the antitumor function of CD4+ T cells. Pharmacological inhibition of PERK in tumor cells can effectively enhance the antitumor function of CD4+ T cells; thus, PERK is a promising immunotherapy target that deserves further study.

In cancers, ER stress arises as an adaptive response to intrinsic oncogenic pressures and extrinsic microenvironmental stressors, enabling tumor survival via the UPR. Conversely, chronic ER stress becomes a pathological consequence of accumulated cellular damage, metabolic dysregulation, or therapeutic interventions, triggering apoptosis or immune modulation. Thus, its role is context-dependent and shaped by the interplay between tumor-intrinsic vulnerabilities and external pressures. Moreover, ER stress plays a dual role in cancer biology, acting as a double-edged sword through its regulation of the UPR. While adaptive UPR activation promotes tumor survival by enhancing metabolic reprogramming, stress tolerance, and immune evasion, sustained ER stress triggers proapoptotic signaling via pathways such as PERK/ATF4/CHOP and IRE1/JNK, indicating therapeutic potential. Mechanistically, ER stress intersects with oncogenic drivers, immune modulation, and metabolic adaptations, shaping tumor progression and therapy resistance across diverse cancers. Targeting UPR components or combining UPR inhibitors with immunotherapies holds promise for precision oncology. However, challenges remain in balancing prosurvival and pro-death UPR outputs to avoid off-target effects. Future studies should elucidate the spatiotemporal dynamics of ER stress in the tumor microenvironment and validate novel therapeutic strategies.

Cardiovascular diseases

Cardiovascular diseases are leading causes of morbidity and mortality worldwide, which drive healthcare utilization and severely impact quality of life. 261 These diseases include atherosclerosis, I/R injury, MI, and heart failure (HF). 262 Pathologic factors in cardiovascular diseases, such as metabolic diseases, hypoxia, and inflammation, can increase the burden of protein folding within the ER, thereby triggering ER stress. In cardiomyocytes and vascular cells, ER stress can be activated under various conditions, some of which are associated with the development of pathology. The cause and effect of ER stress in several cardiovascular diseases are described in detail below (Fig. 5 ). Fig. 5 Role and influence of ER stress in four common types of diseases. Genetic and metabolic abnormalities, inflammation, hypoxia, and other factors can induce ER stress and thus lead to disease. Cardiac pressure overload or ischemia triggers ER stress, leading to protein-folding dysfunction in cardiomyocytes and activation of the UPR, which increases metabolic disturbances, hypoxia, and inflammatory responses in the heart. ER stress reflects both adaptive and maladaptive effects in cardiovascular disease. Early activation of pathways such as the ATF6 or IRE1/XBP1 pathway promotes cytoprotection and restores ER homeostasis, whereas sustained PERK/CHOP signaling often leads to pathological remodeling, apoptosis, and clinical deterioration. ER dysfunction not only leads to protein-folding errors but also affects processes such as mitochondrial function, calcium homeostasis, and cellular autophagy, which in turn trigger neurodegeneration. The aggregation of β-amyloid and tau proteins triggers ER stress, leading to neuronal dysfunction and further aggravating cognitive impairment. Chronic ER stress exacerbates neurodegeneration by driving neuroinflammation, synaptic deficits, and apoptosis. In patients with obesity and type 2 diabetes mellitus, ER stress is often responsible for the impairment of pancreatic β-cell function and insulin secretion disorders, which leads to decreased glucose utilization and loss of pancreatic cell function. Activation of the UPR pathway inhibits normal pancreatic β-cell function and promotes an inflammatory response in adipose tissue. ER stress stems from metabolic overload, triggering maladaptive UPR signaling that disrupts insulin sensitivity, amplifies inflammatory cascades, and disrupts cellular energy homeostasis. There is also a strong association between ER stress and autoimmune diseases, as it not only causes abnormalities in the function of immune cells but also may trigger an autoimmune response as well as an inflammatory response. ER stress is a root cause of disease, fueling chronic inflammation, autoantibody generation, and irreversible tissue damage

Atherosclerosis

Atherosclerosis is a chronic inflammatory vascular disease characterized by the formation of plaques within the intima of blood vessels. 263 ER stress is a hallmark of advanced atherosclerosis, and research on understanding its pathogenesis and identifying biomarkers and therapeutic strategies is urgently needed. In 2001, Nonaka’s team first reported that taurine could resist atherosclerosis by blocking homocysteine-induced ER stress. 264 Mechanistically, the inhibition of GRP78 and PERK expression relieves ER stress, thereby restoring the secretion of extracellular superoxide dismutase, which protects the vessel wall.

Recent studies have shown that fragile X mental retardation protein (FMRP) is induced by ER stress and that one of its sites is phosphorylated. 265 This site enhances the translational repression of FMRP binding to mRNA but inhibits macrophage cholesterol efflux and apoptotic cell clearance upon activation of IRE1. In contrast, pharmacological inhibition by the IRE1 kinase-specific inhibitor AMG-18 blocked IRE1 kinase-FMRP signaling and phenocopied the lack of FMRP in macrophages, preventing atherosclerosis progression. ox-LDL can elicit ER stress-mediated IRE1/XBP1-induced inflammatory responses in a calcium-dependent manner in the cytoplasm and is a key factor in the development and progression of atherosclerosis. 266 Recent studies revealed that the deletion of adipose TG lipase (ATGL) in endothelial cells resulted in the upregulation of basal and palmitate-induced ER stress, with significant changes in the associated factor XBP1. 267 Mechanistically, loss of ATGL leads to the production of ER stress in endothelial cells, which increases lesion size. ER stress enhances the proinflammatory response of endothelial cells, which leads to the accumulation of neutral lipids in the vasculature, thus contributing to the worsening of atherosclerosis.

In 2018, the homocysteine-responsive ER protein (Herp) was used to understand the progression of atherosclerosis. 268 Lin et al. reported that the ATF6 axis of ER stress was significantly activated and induced a phenotypic transition in smooth muscle cells (SMCs) in mice fed a high methionine diet. However, in Herp-deficient mice, Lin et al. reported that atherosclerotic lesions were reduced in the aortic sinus and throughout the aorta; thus, the inhibition of Herp effectively prevented the development of atherosclerosis. Recently, C/EBPβ was shown to attenuate lipid-mediated ER stress and apoptosis. 269 C/EBPβ has potent inhibitory effects on ATF4 and ATF6 and has been shown to block the development of atherosclerosis and macrophage foam cell formation. Abe et al. reported a possible association between membrane-associated guanylate kinase with inverted structural domain structure-1 (MAGI1) and atherosclerosis. 270 They used microarray screening to reveal the critical role of MAGI1 in the ER stress response. The results showed that MAGI1 can regulate endothelial cell activation and form a complex with ATF6 to regulate ER stress and apoptosis, key molecular events in atherosclerosis. Moreover, the expression of XBP1, a hub molecule in this network, is downregulated without MAGI1. 271 In addition, researchers have shown that MAGI1 can directly bind to ATF6, a transmembrane protein involved in the ER stress response, and regulate the nuclear translocation of ATF6, which also validates the link between MAGI1 and atherosclerosis.

ox-LDL is also frequently used as a classical factor to mimic atherosclerosis in vitro. Aldehyde dehydrogenase 2 (ALDH2) has a unique function in inhibiting atherosclerosis progression by attenuating ER stress and SMC apoptosis. 272 Experimentally, ox-LDL was found to promote the upregulation of the ER stress marker PERK, suggesting that ER stress plays an important role in the development and progression of atherosclerosis. Recent findings by Kaw et al. suggest that smooth muscle cell (SMC) α-actinin missense mutations can lead to increased atherosclerosis. 273 Mutations in ACTA, the gene encoding SMC, caused elevated intracellular cholesterol levels, inducing ER stress, specific activation of PERK, and a significant increase in the activities of ATF4 and KLF4 in downstream signaling. ER stress enhances atherosclerosis-associated SMC phenotypic regulation, including increased plaque formation. In addition, a comparative study revealed that CHOP, a downstream factor of PERK, may play a role in the progression of atherosclerotic plaques. 274 Its activation in unstable plaques was confirmed by the finding of significantly elevated immunostaining levels of the CHOP factor, which induces ER stress that increases SMC and macrophage apoptosis. Recently, insulin receptor substrate 1 (IRS-1) has been used to study the effects of ox-LDL exposure on atherosclerosis. 275 In the ox-LDL-induced disease model, the expression of the ER stress biomarkers CHOP and eIF2α was significantly lower in endothelial cells than in those without IRS-1. IRS-1 inhibited ER stress and apoptosis by activating the AKT1/FOXO1 axis, thereby preventing ox-LDL-induced atherosclerosis. In addition, IRS-1 significantly enhanced the proliferative activity of endothelial cells while inhibiting apoptosis, suggesting that IRS-1 can potentially resist ER stress and atherosclerosis development.

Ischemia/reperfusion injury

Myocardial I/R refers to the pathological process in which the ischemic myocardium can regain normal perfusion. The ER, as a reservoir of calcium ions, has gradually become the focus of ameliorating I/R injury. In 2006, Martindale et al. identified for the first time a cardioprotective mechanism of ER stress during I/R. 276 The ATF6 branch of the UPR is activated in the heart, and its induced expression of GRP78 and GRP94 better restores I/R function and significantly reduces necrosis and apoptosis.

Recent studies have shown that ALDH2 can be used as a drug target to alleviate I/R injury and that the inhibition of ER stress plays a key role in this mechanism. 277 ALDH2 deficiency leads to the upregulation of ER stress-related genes, including CHOP and GRP78, which exacerbates myocardial I/R injury. Yang et al. reported that ALDH2 effectively removes endogenous aldehydes, which can consequently attenuate the ER stress-induced formation of neutrophil extracellular traps (NETs), thereby preventing I/R injury. In a rat experiment, the sarcoplasmic reticulum Ca2+ ATPase pump (SERCA2a) ameliorated myocardial I/R injury in rats by inhibiting ER stress. 278 Given the significantly lower prevalence of CHD in premenopausal women, estrogen upregulates the expression of SERCA2a, which inhibits the expression of the ER stress-related proteins CHOP, CRT, caspase-12, and GRP78. These findings provide new potential targets for drug development to ameliorate I/R injury.

However, not all ER stress is deleterious, as Jin et al. revealed the protective effect of the ATF6-mediated ER stress response against I/R injury. 118 Blocking the signaling pathway of ATF6 resulted in increased damage to and decreased function of mouse cardiomyocytes after I/R. The reason for this is that increased ROS mainly causes cardiac I/R injury, but ATF6 induces a variety of antioxidative stress genes, such as catalase, which can reduce ROS. In addition, the ATF6-dependent increase in BiP may also be related to its ability to protect tissues such as the heart from I/R injury. ATF6 branching adaptively reprograms endoplasmic membrane protease homeostasis by inducing a wide range of protective response genes, thereby reducing cardiomyocyte death and providing cardiac protection against I/R injury. 279 This novel mechanism suggests that the ER stress response reduces myocardial I/R injury, validating the potential of the pharmacological activation of ATF6 in the treatment of I/R injury.

Myocardial infarction

MI is a disease in which the myocardium is necrotic due to acute obstruction of the coronary arteries, resulting in insufficient blood supply to the corresponding myocardial region. 280 Correction of ER stress allows the cardiomyocyte reticular network to restore energetic and/or trophic homeostasis and avoid cell death. This property is an important target for the treatment of MI. 281 In 2006, Thuerauf et al. demonstrated for the first time that hypoxia-induced ER stress may be involved in myocardial protection. 282 They reported that, compared with healthy hearts, hearts of MI model mice presented increased GRP78 expression in cardiomyocytes near the infarct area, which promoted cardiomyocyte survival.

Liu et al. reported that all 3 UPR branches are activated after MI and that pharmacological inhibition of PERK prevents the downregulation of cardiac Na+ and K+ channels and reduces deleterious electrical remodeling. 283 Therefore, inhibition of the PERK axis of the UPR prevents selective cardiac ion channel downregulation and protects against MI, a novel therapeutic strategy. 284 Similarly, the inhibition of CHOP, a factor downstream of PERK, attenuated ventricular remodeling after acute MI. 285 A recent study demonstrated for the first time that MI induces significant adipocyte ER stress and endocrine dysfunction by releasing small extracellular vesicles enriched in the miR-23-27-24 cluster. 133 ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3) was identified as a downstream factor of ATF6 and MI-induced activation of PERK/CHOP and ATF6/EDEM in adipocytes. The administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress in animal experiments, which may be an effective therapeutic pathway to ameliorate MI. Mali et al. reported that initiating tyrosine kinase activity of epidermal growth factor receptor (EGFR) may contribute to the adverse effects of ER stress in patients with diabetic MI. 286 In addition, the results showed that inhibition of EGFR significantly reduced infarct size and ER stress induction, suggesting that ER stress is a downstream mechanism of EGFR and that its use as a target may provide a new therapeutic strategy for MI injury.

The protective effect of ATF6 has also been demonstrated in MI. Toko et al. administered an ATF6 inhibitor to mice and reported that the survival rate at 14 days after MI was reduced and that cardiac function was further decreased. 287 Experiments have demonstrated that pharmacological inhibition of ATF6 leads to left ventricular dilatation and decreased cardiac function in the mouse heart, confirming the cardioprotective capacity of activating the ER stress response factor ATF6 under pathological conditions. 288

Heart failure

HF is a disease caused by a malfunction of the pumping function of the heart, resulting in the inability of the heart to meet the basic metabolic needs of the entire body. Over the past decade, ER stress has emerged as an important mechanism in the pathogenesis of cardiovascular diseases, including HF. 289 In 2004, Okada et al. reported for the first time that CHOP-dependent pathways are activated in failing hearts, suggesting that prolonged ER stress may lead to cardiomyocyte apoptosis, resulting in HF. 23

Protective ER stress is sometimes beneficial in pressure overload-mediated cardiac remodeling. The specific and protective effects of IRE1 on HFs were first demonstrated by Steiger et al. 290 Transient activation of IRE1/XBP1 in mouse cardiomyocytes preserved cardiac function and reduced the fibrotic area, and this strong but transient adaptive ER stress response resulted in attenuated inflammatory and pathological gene expression. Binder et al. reported that p21-activated kinase 2 (Pak2)-deficient mice exhibit defective ER stress and cardiac dysfunction. 291 Gene array analysis revealed that Pak2 regulates ER function via the IRE1/XBP1 axis by inhibiting protein phosphatase 2A activity, a protective ER stress response. The activation of Pak2 restores ER function and thus protects the heart from failure; thus, Pak2 could serve as a novel therapeutic target for the cardioprotective ER stress response.

The PERK arm exerts deleterious effects primarily on HFs, increasing the risk of sudden death in patients by increasing mRNA degradation, leading to a decrease in Na+ channels, proteins, and currents. 292 The angiogenic factor AGGF1 can modulate ER stress-related signaling by inhibiting the activation of PERK/eIF2α/ATF4/CHOP, which reduces cardiac cell death and attenuates HF. 293 Atorvastatin was shown to be very effective in inhibiting CHOP as well as other ER stress components, including GRP78, caspase-12, and DDIT3, to protect cardiomyocytes. 294 These findings support the potential therapeutic value of targeting ER stress to reduce cardiac remodeling in HF. Recently, ER stress was shown to induce cardiac dysfunction through altered cardiomyocyte structure and mitochondrial function. 295 In mouse experiments, ER stress in cardiomyocytes led to a significant reduction in the expression of PGC-1α, a major regulator of mitochondrial biogenesis, which impaired mitochondrial calcium ion uptake and excitation‒contraction coupling. This study demonstrated that mitochondrial calcium ion uptake dysfunction and metabolic abnormalities are key factors in ER stress-induced HF. These results suggest that IRE1 and PERK play crucial roles in maintaining calcium homeostasis, endoplasmic network integrity, and cell survival under stress and are promising options for treating HF.

Overall, ER stress plays a dual role in the pathogenesis of cardiovascular diseases. While ER stress is triggered by pathological factors such as metabolic dysregulation, oxidative stress, and inflammation, it acts as a downstream manifestation of these insults. It also exacerbates disease progression by amplifying inflammatory damage, oxidative stress, and apoptosis, thereby establishing a vicious cycle of cellular dysfunction. Notably, the UPR has both adaptive and maladaptive effects in cardiovascular diseases: early activation of pathways such as the ATF6 or IRE1/XBP1 pathways can promote cytoprotection and restore ER homeostasis, whereas sustained PERK/CHOP signaling often drives pathological remodeling, apoptosis, and clinical deterioration. Experimental evidence, including pharmacological inhibition of ER stress regulators and genetic modulation, such as CHOP-deficient models, highlights ER stress as both a consequence of upstream pathologies and a contributor to disease progression. Thus, targeting specific UPR branches to modulate ER stress represents a promising therapeutic strategy, balancing its dual roles in mitigating cardiovascular disease severity while preserving adaptive cellular responses.

Neurodegenerative diseases

Neurodegenerative diseases worsen over time, with a progressive loss of nerve cells or a gradual loss of function. 296 These diseases include Alzheimer’s disease (AD), PD, and Huntington’s disease (HD). The consequences of ER stress may vary greatly depending on the disease context and alterations in the UPR signaling pathway, and targeting the UPR may have different or even opposing effects on disease progression, which holds promise for interventions to alleviate neurodegenerative diseases. 297 This section explores recent advances in the functional link between ER stress and neurodegeneration (Fig. 5 ).

Alzheimer’s disease

AD is a degenerative disorder of the central nervous system, and the risk of developing this disease increases with age. 298 Increased markers of UPR activation are widespread in the brain tissue of AD patients. 299 In 1999, Katayama’s team reported for the first time how ER stress caused by the presenilin-1 (PS1) gene affects AD. 20 PS1 mutations lead to reduced levels of GRP78 in the brains of AD patients, which increases the susceptibility of nerve cells to apoptosis.

ER stress is usually prominent in the early cytopathology of AD. Lee’s team used RT‒PCR experiments to demonstrate increased splicing of the UPR transcription factor XBP1 in the brain temporal cortex of AD patients. 300 A recent study revealed that XBP1 can ameliorate AD by improving synaptic function and protein homeostasis, and that moderate activation restores the levels of several synaptic proteins and factors involved in the regulation of the actin cytoskeleton and axon growth. 301 XBP1 not only reduces the beta-amyloid load in AD mice but also successfully improves their cognitive deficits, which results in the establishment of adaptive and repair programs.

Most phosphorylated PERK and eIF2α are located in the pyramidal cell band of Ammon’s horn and are often detected in the brains of AD patients. 302 PERK and eIF2α are widely activated in the hippocampus, which increases the risk of disease. Yang and colleagues reported a detrimental effect of chronic PERK signaling on synaptic function in an AD mouse model because PERK exacerbates de novo protein synthesis deficits and cognitive deficits caused by metabotropic glutamate receptor 5 damage. 303 Recent studies suggest that 2-deoxyglucose may be a promising drug for treating memory dysfunction in AD. 304 Glucose restriction reduces ER stress in neurons by decreasing ATF4 expression, leading to increased gene transcription related to plasticity, cognitive resilience, and protein homeostasis. Baleriola et al. reported that ATF4 proteins and their transcripts are more frequently expressed in axons in the brains of AD patients. 305 However, maintaining PERK/eIF2α/ATF4 expression at low levels can protect neuronal cells, demonstrating the positive role of the moderate UPR in intraaxonal translation during neurodegeneration.

Parkinson’s disease

PD is a disorder characterized by motor dysfunction and eventual progression to cognitive dysfunction and involves more complex protein aggregation than does AD. 306 Abnormal UPR signaling is a distinctive feature of PD. In 2001, Chun et al. elucidated for the first time the pathogenic mechanism by which chronic exposure to manganese induces PD, which is attributed to the elevated levels of BiP in the ER stress response induced by manganese, leading to cell death in nigral dopaminergic neurons. 307

Early studies revealed that mild ER stress protects the seminal system in PD mice via a mechanism in which moderate activation of the IRE1/XBP1 pathway triggers autophagic responses in vivo. 308 This protection increases resistance to the exogenous apoptotic injury required for PD neuroprotection. However, in most cases, sustained ER stress is the causative agent of PD. Zeng et al.‘s study of thioredoxin-1 (Trx-1) revealed that its downregulation exacerbated PD, which was attributed mainly to the activation of IRE1-induced ER stress by 1-methyl-4-phenylpyridinium ion (MPP(+)) due to the downregulation of Trx-1. 309 A recent report revealed that Trx-1 can also inhibit IRE1 activation in PD by targeting heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) chaperone complexes. 310 These results suggest that Trx-1 may be a potential target for the treatment of PD. In addition, El Manaa’s team reported that XBP1 expression is elevated in the brains of PD patients, possibly due to a combination of ER stress and mitotic dysfunction. 311 The activation of XBP1 upregulates PTEN-induced kinase 1 (PINK1) expression in neuronal cells at the transcriptional level, which leads to the disruption of mitotic control under PD conditions. Misfolded glucocerebrosidase protein induces ER stress and subsequent UPR responses, impairing the autophagy-lysosomal pathway. This leads to the accumulation and diffusion of α-synuclein and promotes neurodegenerative changes leading to PD. 312

In addition, α-syn tends to accumulate in the ER lumen and induce ER stress, possibly through aberrant associations with chaperone proteins. 313 α-syn inhibits the incorporation of ATF6 into COPII vesicles, and the reduction in ATF6 signaling through this physical relationship leads to a decrease in ERAD function and an increase in proapoptotic signaling.

A recent study revealed that leucine-rich repeat kinase 2 protein (LRRK2) impairs calcium homeostasis in the ER environment of astrocytes, leading to intense ER stress. 314 The mechanism involved is increased mRNA and protein levels of PERK/CHOP, which further increase the toxicity of α-syn and may contribute to PD development. A further study of LRRK2 by Yao et al. revealed that it can also interact with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-beta1) to induce ER stress. 315 The significant upregulation of the related factors ATF4/CHOP and GRP78 revealed a role for LRRK2 in inducing ER stress, and intense stress ultimately led to neuron death in PD patients.

Huntington’s disease

HD is an autosomal dominantly inherited neurodegenerative disease. 316 The disease was discovered by the American medical scientist George Huntington in 1872. 317 Moderate control of the intensity of the UPR can effectively improve HD via Huntington’s protein accumulation. In 2002, Nishitoh and colleagues first identified the role of ER stress in HD. 318 PolyQ, which is pathogenic in length, activates ASK1 through the IRE1 pathway during ER stress, which activates JNK and induces neuronal cell death.

Huntington’s protein continuously activates IRE1 signaling during ER stress in the striatum, triggering neuronal loss and leading to the adverse effects of HD. 319 However, Hyrskyluoto et al. reported that ubiquitin-specific protease 14 (Usp14) could inhibit Huntington’s protein buildup, which was accompanied by a reduction in ROS and ER stress. These findings suggest that Usp14 has a role in counteracting Huntington’s protein toxicity. Vidal et al. reported that XBP1 deficiency was associated with improved neuronal survival and motor performance in cellular and animal models of HD. 320 XBP1 expression leads to the impairment of its downstream factor, Forkhead box O1 (FoxO1), and the inhibition of FoxO1, a key transcription factor that regulates neuronal autophagy, leads to diminished resistance to HD and exacerbates this condition. Therefore, targeting the UPR transcription factor XBP1 by regulating autophagy may be a feasible way to prevent HD.

Huntington protein fragments can alter ER morphology, leading to ER expansion and a stress response. 321 Experiments revealed that the abundance of the ER stress signal ATF6 and the phosphorylation of eIF2α were significantly elevated in the striatum of HD mice. When the processing and transcriptional activity of ATF6 are increased, the prosurvival UPR function of striatal neurons is increased. 322 Naranjo’s team determined that silencing downstream regulatory element antagonist modulators can induce ATF6 signaling activation to promote early neuroprotection in HD.

In conclusion, emerging evidence highlights the pivotal role of ER stress in neurodegenerative diseases. ER stress is a root cause of neuronal dysfunction and is initiated by the accumulation of misfolded proteins that disrupt proteostasis and activate the UPR. Chronic ER stress exacerbates neurodegeneration by driving neuroinflammation, synaptic deficits, and apoptosis, as evidenced by the dysregulation of UPR pathways in these disorders. Therapeutic interventions targeting ER stress modulation, such as enhancing adaptive UPR components or suppressing maladaptive signaling, hold promise for alleviating neurodegenerative diseases. Thus, ER stress serves both as a mechanistic origin of neurodegenerative disease initiation and a dynamic contributor to pathological cascades, positioning it as a critical therapeutic target and biomarker for neurodegenerative disorders.

Metabolic diseases

Metabolic diseases are a group of disorders characterized by metabolic abnormalities. 323 These diseases are caused by the accumulation or deficiency of certain metabolic substances, such as sugars, fats, and proteins, when biochemical processes in the body are impaired. The function of the ER as a site for the exchange of ions, lipids, and metabolites is particularly critical. 324 This chapter describes the role of ER stress in three common metabolic diseases, namely, IR, type 2 diabetes (T2D), and obesity (Fig. 5 ).

Insulin resistance

IR refers to the weakening of the physiological role of insulin in the body, mainly manifested as a decrease in the efficiency of glucose uptake and utilization by insulin, and is a common pathological mechanism for the development of a variety of metabolism-related diseases. 325 Recent findings suggest that ER protein misfolding and subsequent activation of UPR signaling play key roles in the pathogenesis of IR. 326 In 2004, Ozcan et al. demonstrated for the first time in mice that deficiency of the transcription factor XBP1, which regulates the ER stress response, results in IR. 22

In a recent study, Yue’s team analyzed the effect of triphenyl phosphate (TPHP) on hepatic glucose homeostasis. 176 This study revealed that TPHP exposure induced ER stress, significantly increasing the expression levels of XBP1, CHOP, and ATF4. The TPHP-induced impairments in glucose uptake and glycogen synthesis were reversed by the use of ER stress inhibitors, and both postprandial glucose levels and insulin sensitivity were partially restored. These results suggest that TPHP induces hepatic ER stress and IR in a concentration-dependent manner. Obesity is a major causative factor of IR. Functional changes in adipose tissue were examined by mimicking obesity with a high-fat diet, and the upregulation of CHOP expression was found to increase ER stress. 327 In CHOP-deficient mice, despite similar macrophage infiltration, adipose tissue macrophages tend to be anti-inflammatory with M2-type polarization, and M2-type macrophages suppress inflammation and improve insulin sensitivity by secreting Th2 cytokines. In vitro experiments revealed that CHOP knockdown reversed the ER stress-induced downregulation of IL-13 and lipocalin, confirming that CHOP regulates adipocyte function and the microenvironment through cell-autonomous mechanisms. In addition, miR-379 can play an important role in high-fat diet-induced IR through mitochondrial dysfunction, the PERK/CHOP pathway of ER stress, and impaired angiogenesis. 328 In recent studies, ER-localized methionine sulfoxide reductase B3 (MsrB3) has been shown to protect cells from oxidation and ER stress; thus, MsrB3 may be a potential target for treating diet-induced IR. 329

Type 2 diabetes

T2D, the most common type of diabetes, is a chronic disease caused by insufficient or less efficient use of insulin. 330 Studies in recent years have shown that ER stress-related proteins are also involved in the pathogenesis of T2D, inducing different degrees of IR and hyperglycemia caused by insulin secretion dysfunction. 331 In 2001, Harding’s team first reported that PERK was highly expressed in the mouse pancreas and increased the phosphorylation of eIF2α, leading to an increase in ER stress-induced pancreatic cell death, which promoted the development of T2D. 332

Nie and colleagues reported that procyanidin B2 (PCB2) attenuated three pathways (IRE1, ATF6, and PERK) associated with high glucose-induced ER stress in human vascular endothelial cells, which may constitute a novel strategy for treating T2D. 333 Recent studies have shown that abnormal vascular endothelial function in the offspring of rats with diabetes mellitus is associated with increased ER stress. 334 The mechanism may involve the downregulation of 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling, an upstream regulator of ER stress, which increases the expression of IRE1, ATF6, and PERK/elF2α, leading to metabolic function abnormalities. Yalcinkaya et al. demonstrated that sustained ER stress can lead to loss of pancreatic cell function through mouse pancreatic islet B-cell studies. 335 High-density lipoprotein (HDL) alone can prevent the onset of T2D via the elimination of the splicing of the ER stress-related gene XBP1, which in turn has antidiabetic effects by inhibiting ER stress.

Physical activity positively modulates the metabolic response in diabetic patients, which is attributed to attenuating ER stress and improving insulin signaling. 336 T2D-induced mitochondrial damage and worsening of ER stress can be attenuated by physical exercise, with ATF6 being the most pronounced change, and it is expected to be a new therapeutic target for T2D.

Early studies revealed that activation of the PERK/CHOP pathway in response to ER stress exerted a proapoptotic effect on pancreatic islet B cells. 337 The protein expression levels of CHOP and BiP are also significantly increased in T2D patients with islet B-cell failure. 338 T2D is triggered by impaired islet B-cell function due to ER stress, leading to absolute or relative insulin secretion deficiency. In addition, curcumin enhances exercise-induced attenuation of ER stress, mainly by reducing the expression levels of BiP and CHOP. 339 Zhang’s team identified a new potential target for T2D therapy. 340 Thyroid adenocarcinoma-associated protein (THADA) is strongly activated in T2D patients, contributing to sustained ER stress in pancreatic islet B cells, followed by activation of the PERK/ATF4/CHOP axis, which exacerbates apoptosis. The most direct manifestation of this is that knockdown of the PERK gene in mice improves the progression of T2D. 341 Selenium nanodots (SENDs) are expected to act as antioxidants to rescue islet B cells from T2D patients by restoring mitochondrial autophagy and attenuating ER stress. 342 SENDs strongly inhibit the transcription of PERK/eIF2α/ATF4/CHOP pathway-associated mRNAs by increasing glutathione peroxidase 1 (GPX1) expression, which can abrogate ER stress very efficiently and thus maintain the functional stability of islet B cells. The interaction of the PERK pathway with T2D has been explored, with IRE1 and ATF6 awaiting more studies in the future.

Obesity

Obesity is defined as the amount of stored fat in the body that exceeds 20% or more of the ideal body weight and is a chronic metabolic disease caused by the interaction of multiple factors, including genetic and environmental factors. 343 Over the past two decades, a large body of evidence has supported the role of adipose tissue ER stress in human metabolic diseases and pointed to the possibility of treating obesity and related diseases. In 2004, Ozcan’s team first elucidated the mechanism of obesity-induced ER stress. 22 This study revealed increased phosphorylation of PERK and eIF2α in high-fat diet-induced obese mice, which demonstrated the production of ER stress.

Adipose tissue macrophages are key players in metabolic inflammation, and macrophage IRE1 has been shown to promote their selective activation and regulate M1–M2 polarization. 344 Bone marrow-specific IRE1 activation manifests as sustained ER stress, which damages brown adipose tissue activity, thereby inducing the development of obesity. Leptin secretion plays an important role in regulating hypothalamic circuits and metabolism, directly affecting obesity. 345 Recently, Park performed a new analysis of the mechanism of action of leptin. Leptin-deficient mice exhibit elevated hypothalamic ER stress, including that of XBP1, ATF6, ATF4, and GRP78, as early as post-natal day 10. 346 After the administration of the ER stress inhibitor taurine deoxycholic acid, metabolic diseases and body weights of the mice significantly improved.

In obese patients, the expression levels of the ER stress-related proteins ATF6 and CHOP are successfully reduced via a low-calorie diet program, which is accompanied by the restoration of calcium ion pools. 347 This finding reflects the attenuation of chronic ER stress and mitochondrial dysfunction and has the potential to serve as a potential target for the treatment of metabolic complications of obesity. Moderate caloric restriction modulates PERK/EIF2A/CHOP expression levels in subcutaneous adipose tissue, reducing ER stress and ameliorating obesity-related metabolic changes. 348 Therefore, weight reduction through caloric restriction may be a generally acceptable strategy to reduce ER stress in obese patients while preventing other complications. A study by Tirosh et al. also revealed increased hepatic ER stress in mice fed a high-fat diet and increased expression of connexin 43 (Cx43) in response to obesity. 347 Chronic ER stress in hepatocytes induces the upregulation of Cx43 through the activation of GRP78 and eIF2α, which triggers cell‒cell coupling, leading to ER stress in other cells due to ER dysfunction. These results suggest that intercellular transmission of hepatic ER stress in obese patients may interfere with systemic metabolic homeostasis. These findings emphasize the importance of ER stress-related pathways in metabolic regulation early in life.

In summary, the intricate interplay between ER stress and metabolic disorders underscores its dual role as both a pathogenic driver and a consequential hallmark of conditions. ER stress arises from metabolic overload, triggering maladaptive UPR signaling that disrupts insulin sensitivity, amplifies inflammatory cascades, and compromises cellular energy homeostasis. While ER dysfunction originates from imbalances in nutrient metabolism, it subsequently manifests as a pathological feature, perpetuating cycles of metabolic dysregulation. Interventions aimed at restoring ER protease inhibition through UPR regulation, enhanced redox balance, or regulation of stress-reactive genes are promising pathways for reducing disease severity. Elucidating the temporal and tissue-specific dynamics of ER stress in metabolic contexts remains critical for developing targeted therapies to address these escalating global health challenges.

Autoimmune diseases

Autoimmune diseases are disease states resulting from an immune response by the body’s immune system against its components, including RA, multiple sclerosis (MS), and inflammatory bowel disease (IBD). 349 These diseases usually involve all body systems, including blood, joints, muscles, bones, and soft tissues around the joints. 350 Once diagnosed, patients should be treated promptly to avoid further progression of the disease, which can damage tissues, organs, or systems. 351 In recent years, it has been reported that ER stress plays a crucial role in the pathogenesis of autoimmune diseases. ER stress is an important mediator of immune cell dysregulation, the activation of proinflammatory pathways, and cellular tissue damage. 13 Understanding this relationship may provide new avenues for targeted therapies to treat this disease (Fig. 5 ).

Rheumatoid arthritis

RA is an autoimmune disease that is pathologically based on synovitis and may eventually lead to joint deformity. 352 ER stress has been found to have an important effect on RA and may be involved in the pathogenesis of RA through synovial cell proliferation and proinflammatory cytokine production. 353 In 2004, Bodman-Smith and colleagues demonstrated for the first time that the ER stress protein BiP is involved in the pathogenesis of RA, as BiP was found to be present in the serum of RA patients and to stimulate synovial T-cell proliferation. 24

To diminish the pathogenicity of fibroblast-like synoviocytes (FLSs), Qi’s team used zinc ferrite nanoparticles targeting fibroblast-activating proteins (FAP-ZF-NPs) in an attempt to treat RA. 354 It enhances FLS apoptosis by appropriately activating the ER stress response and mitochondrial damage through the IRE1/XBP1 and PERK/ATF4/CHOP pathways. In addition, due to the ferrous nature of the FAP-ZF-NPs, the magnetothermal effect could further increase ER stress and mitochondrial injury to improve therapeutic outcomes. However, strong ER stress needs to be suppressed; otherwise, an inflammatory response is generated to exacerbate RA. For the first time, Savic’s team demonstrated that XBP1 activation is associated with RA and that this activation is dependent on toll-like receptors (TLRs). 355 Recent studies have shown that ER stress enhances the expression of inflammatory cytokines and vascular endothelial growth factors in synovial fibroblasts (SFs) stimulated by different TLR ligands, leading to persistent inflammation in RA patients. 356 Rational inhibition of XBP1 reduces the expansion of T helper (Th)1/Th17 cells, a pathway that may serve as a therapeutic target for RA. In addition, the expression of DERL3, an ER-related degradation component in the SF, is elevated in RA patients, and its inhibition can prevent the activation of NF-κB and attenuate the inflammatory response. 357 Furthermore, Yoo et al. reported that synoviocytes in RA express relatively high levels of GRP78 and that the inhibition of Grp78 transcripts increases synoviocyte apoptosis, which has an inhibitory effect on arthritis. 358

Multiple sclerosis

MS is a chronic inflammatory demyelinating autoimmune disease of the central nervous system in which the immune system is involved in its development and progression. 359 Although some studies have shown that ER stress plays a role in MS, research in this area has not been sufficient in recent years. 360 In 2006, Lin et al. first elucidated the role that interferon-gamma-mediated ER stress plays in MS. 361 Interferon-gamma leads to PERK dysfunction, which severely inhibits myelin regeneration and has a deleterious effect.

The activation of ER stress, especially the eIF2α/CHOP pathway, is detected in retinal ganglion cells (RGCs) at the early stage of MS. 362 Sustained ER stress triggers neuronal and glial apoptosis and may also release self-antigens to stimulate further autoimmune responses. Significantly increased RGC survival was found in animal experiments in CHOP knockout mice and mice overexpressing XBP1, suggesting a neuroprotective effect of eIF2α/CHOP inhibition and XBP1 activation against MS. To alleviate the neuropathic pain caused by MS, Yousuf et al. reported that ER stress in neurons may be one of the sources of pain. 363 In MS tissues, the protein levels of XPB1, as well as BiP, are increased, so an attempt was made to inhibit ER stress via the use of 4-PBA. 364 The phosphorylation levels of eIF2α, CHOP, and XBP1 were significantly reduced after the administration of 4-PBA, which effectively alleviated ER stress to reduce nociceptive hypersensitivity.

Inflammatory bowel disease

IBD is an idiopathic bowel disease involving the ileum, rectum, and colon. 365 ER stress was found to regulate the function of immune cells by activating the UPR. 366 In 2006, Shkoda’s team first reported elevated levels of GRP78 expression in the intestinal epithelial cells of IBD patients, suggesting the activation of the ER stress response. 367 In addition, they reported that IL-10 could inhibit the mechanism of the inflammation-induced ER stress response by regulating ATF6 nuclear recruitment to the GRP78 gene promoter, which provides a new strategy for the treatment of IBD.

Group 3 innate lymphoid cells (ILC3s) are commonly found in the gut and have been shown to be correlated with IBD in a recent study. 368 Appropriate activation of the IRE1/XBP1 pathway in ILC3s contributes to their cytokine expression and maintenance of intestinal homeostasis; additionally, IRE1 deficiency results in intestinal tissues being more susceptible to infection and colitis. In a recent report, Ke and colleagues screened microbiome molecules with UPR activity based on XBP1, including ER stress response inducers (acylated dipeptide aldehydes and bisindolylmethane derivatives) and inhibitors (soraphen A). 369 The experimental results suggest that these metabolites may contribute to gut ER homeostasis and provide mechanistic insights into the relationship between the microbiome and inflammatory diseases.

Like in other diseases, ATF6 also plays a protective role in IBD. Ranjan et al. demonstrated that UPR-associated responses can orchestrate the innate immune response, where ATF6 deficiency leads to impaired intestinal bacterial clearance and increased risk of infection and inflammation. 370

In contrast, aberrant activation of the UPR can lead to immune cells in the gut exhibiting proinflammatory properties, increasing the release of inflammatory factors and exacerbating inflammatory responses in the gut. 371 ER stress was found to promote the production of proinflammatory cytokines such as IL-6. 372 The increased protein products of CHOP and GRP78 in IBD patients indicate that ER stress is activated, a state that drives DCs to become proinflammatory cells, as evidenced by increased expression of IL-6, which plays an important role in the inflammatory process of IBD. In addition, ER stress leads to abnormal protein folding in gastrointestinal cells, thereby affecting the integrity of the intestinal barrier. Al-Shaibi et al. reported that anterior gradient 2 (AGR2) deficiency leads to mucin misfolding and that intense ER stress induces mucus barrier defects, triggering IBD. 373 AGR2 deficiency may disrupt mucin 2 (MUC2) processing and impair ER stress regulation, as evidenced by the high expression of GRP78 in patients’ intestinal and gastric mucosa. Microbial changes in the gut are closely related to the onset and progression of IBD, and ER stress may alter the microbial composition by affecting the intestinal environment. However, this type of study is still relatively rare.

In summary, accumulating evidence positions ER stress as a fundamental etiological driver rather than a consequence of autoimmune diseases. ER stress directly initiates and perpetuates pathological cascades by disrupting immune homeostasis through the activation of inflammatory signaling pathways and impairing critical cellular functions. In RA, unresolved ER stress promotes synovial fibroblast hyperactivation and proinflammatory cytokine production; in MS, it compromises oligodendrocyte-mediated myelin repair; and in IBD, it destabilizes intestinal barrier integrity and amplifies mucosal inflammation. These mechanisms underscore ER stress as a root cause of disease, fueling chronic inflammation, autoantibody generation, and irreversible tissue damage. Importantly, therapeutic interventions targeting ER stress mediators and UPR components have the potential to interrupt disease progression by resolving stress-induced immune dysregulation. Thus, ER stress represents a central pathogenic hub in autoimmune disorders, offering actionable molecular targets for precision therapies aimed at restoring immune tolerance and halting organ damage.

Therapeutic targeting of ER stress

ER stress is increasingly recognized as a key factor in the pathogenesis of a wide range of diseases. The intricate balance between ER stress and UPR activation underscores the potential for therapeutic interventions targeting this pathway. This chapter explores various biomarkers and therapeutic approaches to target ER stress. First, we address potential biomarkers of ER stress that can be used to diagnose or monitor treatment outcomes. We discuss agents developed to alleviate ER stress. The actions of these agents range from enhancing protein folding to modulating UPR signaling pathways. Next, we describe clinical trials focused on modulating ER stress. Finally, novel drugs and innovative therapies that are promising for addressing ER stress are highlighted.

Potential biomarkers of ER stress

The identification of ER stress biomarkers has become a critical tool for diagnosing disease and evaluating treatment response. These biomarkers not only reflect the activation status of the UPR but also provide actionable insights into disease progression and treatment efficacy. We categorize ER stress biomarkers according to their molecular properties, present their clinical validation, and describe their application in precision medicine. As dynamic indicators of ER stress, different molecular features generated by the UPR pathway are fundamental components of ER stress biomarkers. Key candidate molecules include ER chaperones, UPR effectors, and apoptosis markers.

GRP78, GRP94, and calreticulin act as chaperones whose expression increases during early ER stress to assist in protein folding. GRP78 has been shown to act as a biomarker of tumor behavior and response to therapy, and its upregulated expression promotes tumor proliferation, survival, metastasis, and resistance to various therapies. 374 Clinically, elevated GRP94 expression is associated with an aggressive phenotype in a variety of cancers and not only promotes survival signaling but also regulates immune responses through multiple pathways. Therefore, GRP94 is a potential molecular marker and therapeutic target for malignant tumors. 375 Calreticulin is a chaperone protein present in the ER, and its exposure plays a broad role in immune surveillance. Studies have shown the potential significance of calreticulin, which is present on the surface of dying tumor cells, as a prognostic biomarker for ovarian cancer patients. 376

Among the effectors, splicing XBP1, phosphorylating eIF2α, and cleaving ATF6 directly correlate with the degree of UPR activation. Detection of spliced XBP1 mRNA is often used as a quantitative method for measuring ER stress. 377 Zhao and colleagues specifically observed XBP1 splicing/activation in TAMs, which led to protumorigenic cytokine expression and promoted CRC growth and metastasis. Therefore, targeting XBP1 signaling in TAMs may be a potential strategy for CRC treatment. 242 In prostate cancer, phosphorylation of eIF2α converts overall protein synthesis to levels that promote aggressive tumor development and is a marker of poor patient survival. 378 Recent evidence emphasizing the protective role of ATF6 in adverse outcomes associated with I/R injury suggests that ATF6 is a biomarker for intervention in a variety of ischemia-associated disorders and that targeting ATF6 intervention has the potential to predict such disorders. 288

Apoptosis, a common outcome of ER stress, is mediated by the PERK pathway through the upregulation of CHOP and caspase-12 during the terminal UPR. 379 , 380 In addition, increased CHOP mRNA in clinical samples is also a biomarker of poor prognosis in chemotherapy-treated rhabdomyosarcoma patients. 381

Many ER stress biomarkers have been used in clinical diagnosis and treatment monitoring. Nourbakhsh et al. reported significantly elevated serum GRP78 levels in patients with T2D (1.3-fold greater than those in controls) and high diagnostic accuracy. 382 In hepatocellular carcinoma, Lim et al. reported that the expression of GRP78 and GRP94 increased with increasing cancer progression and was significantly associated with vascular infiltration and intrahepatic metastasis. 383 In 2010, Bagratuni’s team correlated the gene expression levels of XBP1 unspliced (XBP1u) and XBP1 spliced (XBP1s) with clinical outcomes, with patients with low XBP1s/u ratios predicting high survival. Researchers have also reported that patients with low XBP1s/u ratios respond better to thalidomide treatment, and the survival of patients in the low-ratio group treated with thalidomide was significantly better than that of patients in the conventional chemotherapy group. 384 In addition, ER stress biomarkers are not only diagnostic tools but also tools to guide targeted therapy. XBP1 is highly advantageous for predicting drug response. In 2013, Tiedemann et al. explored the mechanisms of proteasome inhibitor (PI) resistance in MM and reported that myeloma patients with higher levels of XBP1s at baseline responded better to proteasome inhibitors. 385 In monitoring treatment efficacy, Jagannathan and colleagues reported that HSPA5, which encodes GRP78, was highly expressed in patients who did not respond to bortezomib treatment, suggesting that high expression of GRP78 is a potential marker of resistance and that detecting the level of HSPA5 expression in the tumors of first-time patients predicts their probability of responding to bortezomib. Moreover, monitoring the dynamic changes in GRP78 during treatment could provide a basis for adjusting the drug dosage or combining drugs (e.g., adding autophagy inhibitors) to overcome drug resistance. 386

In summary, the identification of ER stress biomarkers not only provides a tool for early diagnosis and typing of the disease but also allows dynamic evaluation of therapeutic efficacy, guides individualized treatment, and promotes the development of drugs targeting the ER stress pathway. With the advancement of multiomics technology, its value in precision medicine will be further enhanced.

Drugs targeting ER stress

The development of preclinical drugs that target ER stress represents a crucial frontier in therapeutic innovation, particularly for diseases characterized by protein misfolding and cellular dysfunction. Recent advances in understanding the molecular pathways involved in ER stress have led to the identification of specific targets for drug development, allowing researchers to create small molecules that can increase chaperone activity or inhibit proapoptotic signaling. By focusing on these pathways, preclinical drug candidates show promise in alleviating the burden of diseases, providing a foundation for future clinical applications (Fig. 6 ). Fig. 6 Common therapeutic agents that target ER stress and modify tissue cells. UPR pathway modulators produce therapeutic effects against different diseases. Common types of inhibitors include inhibitors that target the IRE1 ribonuclease and protein kinase structural domains, ATF6 inhibitors, PERK/eIF2α inhibitors, and BiP inhibitors. The efficacy of these inhibitors is demonstrated by their ability to induce apoptosis in damaged cells, enhance the antitumor function of immune cells, increase antiangiogenic effects, decrease cytotoxicity, attenuate inflammatory responses, reduce nerve cell mortality, and restore cell viability. Classical concurrent chemoradiotherapy is a combination of chemotherapy and radiotherapy used to treat cancer, and combining ER stress inhibitors with chemoradiotherapy can enhance the therapeutic effects of both. In recent years, novel drugs that target ER stress, including cancer vaccines, fluorescent probes, and nanogel drugs, have been developed for the treatment of various diseases

Cancers

Over the past decade, numerous preclinical and cellular studies targeting UPR signaling proteins have developed various inhibitors and chemotherapeutic agents. This section will detail several UPR pathway modulators known to produce antitumor effects across different cancer types. The efficacy of these inhibitors is demonstrated by altered amino acid metabolism, reduced vascular density, and decreased vascular perfusion, all of which contribute to their antitumor activity. 78 Notably, the simultaneous use of multiple target inhibitors against cancer cells has better efficacy. 387 The unique advantages of this combination therapy include controlling tumor progression and metastasis without damaging normal tissue.

Pathway inhibitors

There are two common types of inhibitors of IRE1, including those that target the IRE1 ribonuclease and protein kinase structural domains. IRE1 ribonuclease inhibitors, including B-I09, STF-083010, MKC3946, MKC8866, and 4μ8C, have been extensively tested in CLL, MM, ALL, and ovarian cancer. 78 Sharing a common hydroxy-aryl-aldol (HAA) molecule, these inhibitors selectively target a specific lysine (Lys907) in the structural domain of the RNase, effectively preventing ER stress-induced site-specific mRNA splicing. 388 In a CLL mouse model, B-I09, which targets the IRE1-XBP1 pathway, led to XBP1 deficiency without affecting normal secretory or membrane-bound protein transport (Table 2 ). 35 Combining ibrutinib and B-I09 for treating human CLL has been shown to effectively inhibit leukemia progression without systemic cytotoxicity. 389 Moreover, B-I09 has improved the treatment of c-MYC- and N-MYC-driven malignancies, as demonstrated in model experiments. 390 In 2011, STF-083010 was used in MM studies as a small molecule inhibitor that specifically suppressed IRE1 endonuclease activity without affecting kinase activity. 30 The fourth-generation salicylaldehyde inhibitor MKC8866 targets the RNase structural domain of IRE1 for pharmacological inhibition (Table 2 ). 391 In a mouse model of ALL, the tyrosine kinase inhibitors (TKIs) nilotinib and MKC8866 act together in ALL cells. This combination enhances cell viability through synergistic induction of cytotoxicity. 392 Additionally, Xiao et al. proposed a combination drug approach for treating ovarian cancer last year, with promising results for the immune checkpoint inhibitors (ICIs) AZD1775 and MKC8866 in multiple cell lines and preclinical models of ovarian cancer. 393 The dual action on the UPR signaling pathway significantly enhanced tumor cell apoptosis, surpassing single drug delivery and offering a therapeutic opportunity for synergistic effects between AZD1775 and MKC8866. Finally, 4μ8C gains selectivity by forming an abnormally stable Schiff base with lysine 907 in the structural domain of the IRE1 endonuclease, which blocks substrate access to the active site of IRE1, leading to the inactivation of XBP1 splicing and IRE1-mediated mRNA degradation (Table 2 ). 32 The treatment of hepatocellular carcinoma mice suffering from fibrosis with 4μ8C significantly reduced the tumor burden and restored collagen to healthy baseline levels. Table 2 Delivery strategies for ER stress-targeted drugs Name Category Delivery Pathway Oncolytic viruses Injectable delivery Gene vector PERK/eIF2α B-I09 Injectable delivery Gene vector IRE1/XBP1 Paclitaxel Nanocarrier Nanomicelle eIF2α phosphorylation CB-5083 Nanocarrier Solid lipid nanoparticle ATF6, IRE1/XBP1 Amikagel Nanocarrier Nanoparticle CHOP EMT-NP Nanocarrier Nanoparticle IRE1, CHOP Au/Toy@G3 NGs Nanocarrier Nanogel IRE1/XBP1 ISRIB Biogenic vector Retroviral vector eIF2α phosphorylation MKC3946 Unspecific pLKO.1 shRNA vector IRE1/XBP1 MKC8866 Unspecific pGL3-MYC luciferase reporter plasmid plus either empty vector (pCDNA3) IRE1 RNase domain 4μ8C Unspecific Expression vectors encoding preprotrypsin-FLAG-HsIRE1[19–977] wild type IRE1 endonuclease KIRA8 Unspecific pET-28a vector IRE1 Kinase Fluvastatin Unspecific β-gal-LacZ expression vector GRP78

The second class of inhibitors targets the structural domain of the IRE1 kinase and consists mainly of KIRA6, KIRA7, and KIRA8 of the kinase-inhibiting RNase attenuator (KIRA), which act by binding to the ATP pocket in the kinase structural domain. KIRA6, in a dose-dependent manner, inhibits IRE1 and XBP1 RNA cleavage, thereby improving cell survival under ER stress. 34 KIRA7 has been used in relatively few applications. KIRA8, also known as compound 18, selectively decreases the viability of patient-derived MM cells without significantly affecting normal cells (Table 2 ). 394 In a mouse model of established MM, KIRA8 treatment significantly reduced the tumor burden, demonstrating substantial in vivo efficacy. Notably, KIRA8 also improved the effectiveness of two established first-line antimyeloma drugs, bortezomib and lenalidomide, against MM. Experimental analysis of human MM cells by Yamashita et al. revealed that KIRA8 reduced cell viability and induced apoptosis, whereas its combination with bortezomib had greater antimyeloma effects. 395 KIRA8, in combination with anti-VEGF-A, an effective triple-negative breast cancer (TNBC) treatment, significantly decreases tumor growth, outperforming monotherapy. 218 Notably, compound 18 is the only agent to date that specifically targets cancer-associated fibroblasts (CAFs), a key cellular component associated with cancer progression. By disrupting IRE1, a key regulator within the CAF environment, this compound exerts its antitumor effects. These reports indicate that IRE1 RNase/kinase inhibitors can improve treatment outcomes, particularly in cases of poor chemotherapy response, drug resistance, and disease recurrence. The unique mode of action of these inhibitors offers far-reaching implications for developing revolutionary therapeutic approaches, paving the way for new cancer treatment strategies.

Until Ceapin was developed by Gallagher et al. through a cell-based screening approach, the ATF6 signaling pathway was considered nonpharmacological. 396 It is the first inhibitor to selectively inhibit ATF6α without affecting other signaling pathways in the UPR and even without altering the viability of unstressed cells. Unlike conventional protease inhibitors, Ceapins do not inhibit ATF6α proteolysis and activation but instead eliminate the need for ATF6α trafficking from the ER by relocalizing Golgi-resident S1P and S2P proteases back to the ER. 397 Recently, this team revealed a novel mechanism underlying Ceapin specificity: an organelle-tethering mechanism that fosters a new morphological association between the ER and peroxisomes, paving new pathways for drug development and synthetic biology. 398

Compared with that of ATF6, the activity of the PERK/eIF2α signaling pathway is greater, which has prompted the development of targeted inhibitors. GSK2606414 was reported as the first PERK inhibitor. 33 As an oral, potent, and selective PERK inhibitor, it blocks the UPR pathway, reduces ROS production, and enhances cell viability. 399 In a mouse model, GSK2606414 reactivated T-cell function and reduced mitochondrial ROS in PD-1+ CD8+ TILs, improving CD8+ T-cell viability. 400 Notably, combining GSK2606414 with anti-PD-1 therapy resulted in a 100% survival rate. In addition to its antitumor effects, GSK2606414 has unique efficacy against astrocytes in certain neurological disorders, resulting in increased levels of the autophagy signaling protein P62, accumulation of the dipeptide repeats protein poly (GA) in deep neurons, DNA damage, and the occurrence of nuclear fission. 401 Similarly, GSK2656157 is an ATP-competitive PERK inhibitor. Yodsanit et al. first used GSK2656157 to treat AAA in 2023. 402 In the aneurysmal aortas of AAA patients, PERK is hyperphosphorylated, and the downstream proteins ATF4 and CHOP are significantly upregulated, while GSK2656157 effectively interferes with this process. Designed in 2015, AMG-44 is a potent, selective PERK-only inhibitor for exploring the PERK pathway both in vitro and in vivo. 403 Mohamed et al. evaluated the antitumor effects of GSK2606414 and AMG-44. 144 Mice treated with each inhibitor separately experienced similar tumor growth delays, with AMG-44 notably avoiding pancreatic toxicity. The reduced immunosuppressive activity of MDSCs under the modulation of AMG-44 caused an expansion of tumor-infiltrating CD8+ T cells expressing IFNγ, which greatly enhanced the antitumor capacity of these cells. LY-4, an emerging PERK inhibitor, significantly reduces PERK phosphorylation and nearly 90% reduces tumor growth upon administration. 404 LY-4 treatment is well tolerated in melanoma and has clear therapeutic potential, as evidenced by the absence of pancreatic damage in blood glucose level monitoring.

Recently, discovered, ISRIB is a novel eIF2α inhibitor that activates eIF2B to inhibit eIF2α phosphorylation, improving the prognosis of neurological diseases and finding applications in cancer treatment. 405 In preclinical trials of prostate cancer, ISRIB significantly prolonged the survival of mice with metastatic tumors, although the effectiveness of ISRIB treatment against prostate cancer was transient. 378 It triggers cytotoxicity against aggressive metastatic prostate cancer cells through its selective reversal of the effects of eIF2α phosphorylation, notably without significant side effects. The latest study revealed that combining ISRIB with doxorubicin, owing to its ability to inhibit stress granule formation, significantly attenuates TNBC tumor growth through a synergistic effect. 406 In a study targeting pancreatic ductal adenocarcinoma, the PERK inhibitor GSK2606414 and the eIF2α phosphorylation inhibitor ISRIB significantly inhibited tumor growth with great potential to improve treatment outcomes. 407 In lung cancer, treating tumor cells with both inhibitors substantially decreased survival, mirroring the results observed in pancreatic ductal adenocarcinoma. 408 Given the significant role of pathways such as PERK/eIF2α/CHOP in maintaining organ homeostasis in hypersecretory tissues, it is crucial to consider their effects on normal tissues to minimize potential toxicity during treatment. Specifically, PERK inhibitors such as AMG-44 and LY-4, which are known for their tolerability and robust antitumor efficacy without detectable cytotoxic side effects, offer clear guidance for future inhibitor selection.

Inhibitors against the three UPR pathways have been widely used, and targeted inhibitors of BiP, an essential protein for the initiation of the UPR, are being progressively developed. Given that BiP inhibitors bind to the three sensors of the UPR and render them inactive, there are already clinical applications for BiP inhibitors. KP1339, a ruthenium-based compound and BiP-targeted inhibitor, has shown promising anticancer activity in a phase I clinical trial. 409 Combining KP1339 with sorafenib, a classic liver cancer treatment, induced significant synergistic effects, enhancing tumor cell apoptosis. 410 Recently, KP1339 was also found to trigger ICD features in colorectal cancer, as indicated by PERK and eIF2α phosphorylation, calmodulin exposure on cell membranes, and the release of high mobility group box 1 and ATP. 411 KP1339 has shown preclinical activity across various tumor types, with acceptable tolerance and disease stability, despite some mild side effects. The discovery of KP1339 provides support for the integration of metabolomics with immunotherapy. Despite the obscure role of metal-based drugs in modulating antitumor responses, they offer new possibilities in the burgeoning field of cancer therapy.

Cerezo et al. developed a series of molecules (thiazole benzenesulfonamides) that promote melanoma cell death by targeting the ER stress pathway. Histocompatibility antigen 15 (HA15), which is the main component, is a highly selective BiP inhibitor that interacts only with BiP without affecting IRE1, PERK, or ATF6. 412 HA15 reduces BiP levels in the immunoprecipitated fractions of PERK, IRE1, and ATF6 and inhibits BiP ATPase activity in a dose-dependent manner. Importantly, HA15 is effective against BRAF inhibitor-resistant melanomas and tumor cells with high BiP levels, slowing their progression. A recent study also suggested that genetic inhibition of BiP not only reduces tumor growth but also contributes to tumor suppression by sensitizing colon cancer cells to BRAF inhibitor-induced ER stress and apoptotic responses. 413 Moreover, Samanta et al. reported that YUM70, a hydroxyquinoline analog, induces ER stress-mediated apoptosis in pancreatic cancer by binding to BiP and inhibiting its ATPase activity. 39 YUM70 showed superior efficacy against pancreatic cancer in both in vivo and in vitro experiments, as it selectively inhibited tumor growth without affecting normal tissue. Researchers have combined YUM70 with the clinically approved drugs topotecan and vorinostat to treat pancreatic cancer. This combination revealed strong synergistic effects, increasing both early and late apoptosis. Targeting BiP with HA15 and YUM70 effectively treats lung and colon cancers with KRAS mutations, in addition to pancreatic cancer. 414 These studies provide strong evidence that BiP is a therapeutic target and highlight the potential of YUM70 as a therapeutic agent for pancreatic cancer.

This chapter provides a comprehensive overview of the most commonly used ER stress pathway inhibitors in cancer therapy (Table 3 ). This discussion highlights the dual role of ER stress inhibitors in promoting apoptosis in malignant cells while sparing normal cells, thereby offering a therapeutic window. Overall, targeting ER stress pathways represents a promising strategy in cancer treatment, warranting further investigation into their clinical applications and potential synergistic effects with existing therapies. Table 3 ER stress pathway-related inhibitors Classification Name PMID Instruction IRE1 inhibitor B-I09 24812669 B-I09 is a water-soluble 1,3-dioxane derivative that effectively inhibits the expression of XBP1 and is a potent IRE1 RNase inhibitor. STF-083010 21081713 STF-083010 is a specific IRE1 endonuclease inhibitor without affecting its kinase activity. MKC3946 22538852 MKC3946 is an IRE1 endonuclease structural domain inhibitor that blocks XBP1 mRNA splicing and triggers growth inhibition in tumor cells. MKC8866 30679434 MKC8866 (IRE1-IN-8866), a salicylaldehyde analog, is a specific IRE1 RNase inhibitor with an IC50 of 0.29 μM for human IRE1 in vitro. 4μ8C 22315414 4μ8C (IRE1 Inhibitor III) is a potent and selective IRE1 Rnase inhibitor with IC50 of 76 nM. KIRA6 25018104 KIRA6 is a potent type II IRE1 kinase inhibitor with an IC50 of 0.6 μM. It dose-dependently inhibits IRE1(WT) kinase activity, XBP1 RNA cleavage, Ins2 RNA cleavage, and oligomerization. KIRA7 30625178 KIRA7 is an imidazopyrazine compound that binds to IRE1 kinase (IC50 of 110 nM) and inhibits its RNase activity in a metastable manner. KIRA7 has anti-fibrotic properties. KIRA8 28380378 KIRA8 (IRE1 inhibitor, AMG-18) is a mono-selective IRE1 inhibitor that allosterically attenuates IRE1 RNase activity with an IC50 of 5.9 nM. ATF6 inhibitor Ceapin-A7 27435962 Ceapin-A7 is a selective and highly potent inhibitor of ATF6, which can activate the response to ER stress, with an IC50 of 0.59 μM. PERK/eIF2α inhibitor GSK2606414 22827572 GSK2606414 is an orally available, potent, and selective PERK inhibitor with an IC50 of 0.4 nM, displaying at least 100-fold selectivity over the other EIF2AKs assayed. GSK2606414 impairs GANT-61-induced autophagy in NB cells with MYCN amplification. GSK2606414 exacerbates ER stress-induced apoptosis in HCT116 cells while reducing the apoptosis in SIL1 KD HeLa cells. GSK2656157 23333938 GSK2656157 is an ATP-competitive and highly selective inhibitor of PERK with an IC50 of 0.9 nM in a cell-free assay, 500-fold greater against a panel of 300 kinases. GSK2656157 decreases apoptosis and inhibits excessive autophagy. AMG-44 25587754 AMG-44 is a highly selective and orally active inhibitor of PERK with an IC50 of 6 nM. AMG-44 exhibits 1000-fold and 160-fold selectivity over GCN2 and BRAF, respectively. LY-4 27977682 LY-4 is a PERK-specific inhibitor with an IC50 value of 2 nM and little activity against other eIF2α kinases. ISRIB 23741617 ISRIB is an integrated stress response (ISR) inhibitor that potently reverses the effects of eIF2α phosphorylation. BiP/GRP78 inhibitor KP1339 12778081 KP1339 is a first-in-class ruthenium anticancer agent developed for solid cancers with low side effects. KP1339 induces G2/M cell cycle arrest, DNA synthesis blockade, and apoptosis via the mitochondrial pathway. KP1339 has a high tumor-targeting potential, binds strongly to serum proteins such as albumin and transferrin, and is activated in the reductive tumor environment. Thiazole benzenesulfonamides 27238082 HA15 is the lead compound of Thiazole benzenesulfonamides. The BiP/GRP78/HSPA5 chaperone is a specific target of HA15, leading to melanoma cell death by simultaneously inducing autophagy and apoptosis mechanisms. YUM70 33531374 YUM70 is a potent inhibitor of GRP78 with an IC50 of 1.5 μM. YUM70 induces ER stress-mediated apoptosis in pancreatic cancer. Although YUM70 inhibits GRP78 enzymatic activity, it increases the expression of GRP78 by increasing the chaperone translation mechanism.

Chemoradiotherapy

Classical concurrent chemoradiotherapy is a combination of chemotherapy and radiotherapy used to treat cancer. Lee et al. reported that the expression of the ER stress protein GRP78 has significant prognostic value in neoadjuvant radiotherapy for locally advanced rectal cancer. 415 Combining ER stress inhibitors with chemoradiotherapy can enhance the therapeutic effects of both drugs. Given the frequent overexpression of squalene epoxidase (SQLE) in human cancers, Hong et al. investigated a novel tumor-specific radiosensitizer targeting this enzyme. 416 Inhibiting SQLE to activate PERK/eIF2α-mediated translation triggers an ER stress response, promoting radiosensitization in breast and lung cancer cells. Furthermore, Guo’s team investigated the impact of ER stress pathway gene polymorphisms on the clinical efficacy of radiotherapy in nasopharyngeal carcinoma patients. Statistical analysis revealed that several genes, including XBP1, were significantly associated with primary tumor outcome 3 months after radiotherapy and with the occurrence of radiotherapy-induced myelosuppression and may serve as predictors of the clinical outcomes of radiotherapy in nasopharyngeal carcinoma patients. 417

Immunotherapy

Among common antitumor immunotherapies, ICI therapy has been extensively studied for its role in interfering with the ER to treat cancer. ICI therapy disrupts negative immune checkpoints and activates antitumor immune responses. 418 The antitumor immune response refers to a series of reactions and mechanisms of the body’s immune system against tumor cells aimed at recognizing, destroying, or controlling the proliferation and spread of tumor cells. 419 The discovery of predictive biomarkers is crucial, potentially expanding the range of patients benefiting from immune checkpoint blockade. ICI therapy not only enhances the antitumor immune response but also influences the intrinsic dynamics of the TME. 420

Recent research has shown that drugs targeting ER-associated biomarkers increase the efficacy of anti-PD-L1 immunotherapy. PD-L1, which is synthesized in the ER of tumor cells and is overexpressed in various cancers, enables tumor cells to evade antitumor immunity by inhibiting T-cell-mediated cytotoxicity. 421 Sun et al. reported that hepatocellular carcinoma cells mediate antitumor responses via ER stress-released exosomes. 422 Notably, miR-23a-3p, an upstream microRNA of PD-L1, inhibits T-cell function by upregulating PD-L1 in macrophages. Researchers subsequently revealed the potential of the thyroid adenoma-associated gene (THADA) as a biomarker in colorectal cancer cells. 423 Targeting THADA leads to PD-L1 degradation via the ER, remarkably increasing T-cell-mediated cytotoxicity. An early study indicated that metformin-activated AMPK directly phosphorylates S195 of PD-L1 and that its phosphorylation induces ER stress, which promotes antitumor immunity through PD-L1 degradation. 424 Importantly, ER-targeted therapies have been shown to activate the immune system and enhance anti-PD-L1 therapy, motivating further exploration of ER stress-related biomarkers. 425 Guttman et al. treated tumor-bearing mice with an anti-mouse PD-L1 monoclonal antibody and an IRE1 inhibitor but only partially inhibited tumor progression. 426 Combining these agents was significantly more effective than either treatment alone. Therefore, synergizing IRE1 inhibition with anti-PD-L1 antibody therapy significantly contributes to tumor regression. Additionally, IRE1/XBP1 pathway inhibitors may enhance PD-1 antibody therapy. IRE1/XBP1 pathway inhibitors repolarize M2-TAMs in response to ER stress and oxidative stress, greatly increasing immunotherapy sensitivity. 427 This approach not only slows tumor growth but also enhances the effectiveness of anti-PD-1 therapy.

B-I09, in combination with anti-PD-1 antibodies, particularly targets coactivator-associated arginine methyltransferase 1 (CARM1)-expressing ovarian cancer cells, increasing treatment efficacy. 428 This combination therapy significantly outperformed monotherapy in reducing the tumor load and improving survival in tumor-bearing mice. Additionally, Yang et al. reported that paclitaxel (PTX) treatment activates the PERK/eIF2α pathway, as evidenced by ER stress-related gene expression and immune cell profile analysis in treated tumors (Table 2 ). 429 Consequently, low-dose PTX and PD-1 antibody combination therapy was proposed to stimulate CD8+ T-cell-dependent antitumor immunity, significantly improving treatment efficacy. A study also revealed that SCD1 inhibitors enhance the therapeutic effects of immunotherapy by impairing ER stress. 430 SCD1 inhibitors reduce ER stress, enhancing antitumor T-cell production and increasing the therapeutic effect of anti-PD-1 antibodies. These studies highlight that single anti-PD-1/PD-L1 therapy is insufficient for optimal efficacy, making combination therapy a promising research direction.

Advanced cancer phototherapy techniques, when combined with ICI therapy, inhibit tumor growth. Photosensitizers activate ER stress and ICD, potentiating the antitumor immune response without inducing cytotoxicity. 431 When combined with oxaliplatin, an ICD inducer, researchers reported significant enhancement of tumor immunogenicity. A study has shown that the ER stress response triggers ICD, inducing a protective antitumor immune response, with a significant focus on the PERK axis of the UPR. 432 Mohamed et al. reported that deleting PERK signaling transforms MDSCs into myeloid cells, increasing CD8+ T-cell-mediated anticancer responses. 144 Therefore, pharmacologically inhibiting PERK in melanoma cells stimulates potent activation of antitumor T-cell immunity. Furthermore, eliminating PERK in malignant cells triggers SEC61β-induced apoptosis, inhibiting tumor growth. 433 Consequently, combining ICD with ER-related inhibitors as part of a combinatorial therapeutic strategy shows promising efficacy and prognosis.

In recent years, through optimization and improvement, chimeric antigen receptor (CAR)-T cells have achieved very good results in clinical tumor therapy. 434 Ibanez’s team reported that the ER stress response gene GRP78 may be a promising target for CAR-T-cell therapy. In vitro and in vivo experiments confirmed that GRP78-CAR-T cells can recognize and kill brain tumors, while the significant upregulation of GRP78 in CAR-T cells also increased their therapeutic response. 435 In addition, cell-surface GRP78-targeted CAR-T cells were also demonstrated to eliminate lung cancer tumor xenografts by Wang et al. The results showed that cell-surface GRP78-targeted CAR-T cells could effectively kill lung cancer cells without any recurrence or harmful effects. 436

Cardiovascular diseases

ER stress plays an important role in the development of cardiovascular diseases. When cardiomyocytes are exposed to stimuli such as oxidative stress, ischemia, or inflammation, ER dysfunction may lead to impaired protein folding, which in turn induces apoptosis and cardiac injury. In recent years, researchers have reported that drugs targeting ER stress can effectively improve the prognosis of cardiovascular disease patients. These drugs provide new therapeutic ideas by modulating the folding ability of the ER, enhancing cell survival signaling, or attenuating inflammatory responses, providing new hope for patients with cardiovascular disease.

Atherosclerosis

Salvianolic acid B (SalB), a water-soluble substance and the main bioactive compound in Salvia divinorum, has antioxidant and anti-inflammatory effects and has been used to treat atherosclerosis. 437 Chen et al. demonstrated that SalB pretreatment significantly prevented doxorubicin-induced intracellular calcium ion disturbances, mitochondrial membrane potential disturbances, and elevated levels of ER stress-related proteins in mouse heart cells. 438 This cardioprotective effect mainly attenuated ER stress by inhibiting TRPC3- and TRPC6-mediated calcium overload in cardiomyocytes. 439 Fluvastatin can induce a cytoprotective UPR, as evidenced by the protection of macrophages from hypoxia-induced cell death via GRP78 induction, which contributes to the treatment of advanced atherosclerosis (Table 2 ). 440

Ischemia/reperfusion injury

Many reports have shown that atorvastatin attenuates ER stress-related protein levels. 441 In the presence of myocardial I/R, it can reverse the expression of SIRT1, block the ER stress pathway, and improve cardiomyocyte survival. 442 Metformin, a traditional antidiabetic drug, also reduces cardiac injury during I/R. It attenuates cardiac injury during ER stress primarily by protecting cardiac mitochondria and inhibiting CHOP expression. 443

Myocardial infarction

Ginkgolide K can limit ER stress damage by increasing IRE1/XBP1 activity in cardiomyocytes, which leads to ER-related degradation-mediated clearance of misfolded proteins and increased autophagy. 444 Ginkgolide K was also able to partially inhibit the proapoptotic effects of the IRE1-dependent decrease and the JNK pathway, which could be effective in the treatment of MI.

Heart failure

Recent reports indicate that TUDCA and sildenafil can restore the expression levels of ER stress pathway genes (XBP1, ATF4, and ATF6) and ER stress targets (HSPA5, DDIT3, and DNAJC3). 445 Stabilization of ER function leads to the rescue of mitochondrial respiratory defects, oxidative stress, and apoptosis, which helps early-stage HF patients. George et al. reported that β-adrenergic antagonists reduce ER stress and normalize calcium handling; among these effects, metoprolol improves cardiac function by decreasing the expression level of eIF2α, which is beneficial in HF. 446 Liu et al. assessed apoptosis in the heart after treating mice with the selective eIF2α dephosphorylation inhibitor salubrinal and reported that salubrinal reduced ER stress and myocardial apoptosis, which could be used to treat HF. 447 The inhibition of cGMP-specific phosphodiesterase 5 (PDE5) with sildenafil was shown to have beneficial effects on HF in a study by Gong et al. 448 The main mechanism is that sildenafil inhibits the expression of PERK, GRP78, and XBP1 to prevent ER stress, thereby reducing cardiomyocyte apoptosis.

Other cardiovascular diseases

Curcumin has been frequently reported to prevent a variety of heart diseases. 449 Its cardioprotective mechanism is related to the reduction in palmitate-induced apoptosis in cardiomyocytes, which occurs mainly through the inhibition of ER stress-related signaling pathways through the downregulation of GRP78 and CHOP. 450 Recently, Li’s team validated the principle of tauroursodeoxycholic acid (TUDCA) in the treatment of obese cardiomyopathy, which attenuates intracellular calcium abnormalities and regulates ER stress by downregulating the expression of GRP78, eIF2α, and ATF4. 451 TUDCA can also be used to treat obese cardiomyopathy patients. In addition, TUDCA alleviated myocardial inflammation by inhibiting the IRE1-associated NF-κB pathway, exerting a protective effect on cardiomyocytes, which is very important in the study of cardiovascular diseases. 452 The sodium‒glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin can attenuate ER stress by inhibiting the mTOR pathway. 453 SGLT2 inhibition attenuates elf2α and downstream ATF4 and CHOP signaling, leading to reduced left ventricular apoptosis and fibrosis, a newly recognized cardioprotective mechanism. Dapagliflozin is also used as an SGLT2 inhibitor in the treatment of diabetic patients, and it also reduces the expression of ER stress- and apoptosis-related proteins in high glucose-induced cardiomyocytes. 454 In addition, metformin has been shown to attenuate ER stress in vascular smooth muscle cells by inhibiting the expression of XBP1, eIF2α, and GRP78, thereby alleviating hypertension. 455

In summary, therapeutic strategies targeting ER stress show great promise in the management of cardiovascular disease. Although this topic is still in the research stage, through a deeper understanding of the mechanism of ER stress and its role in cardiovascular disease, more effective and safer drugs are expected to be developed in the future. This will not only improve the quality of life of patients but also help reduce the morbidity and mortality of cardiovascular diseases.

Neurodegenerative diseases

ER stress is a key factor in the development of neurodegenerative diseases. Nerve cells activate the ER stress response when faced with oxidative stress, protein aggregation, and metabolic imbalance, a process that, if uncontrolled, may lead to apoptosis and dysfunction. In recent years, researchers have shown that drugs that target ER stress can provide new therapeutic avenues by improving the folding capacity of the ER, promoting protein degradation, and reducing neuroinflammation.

Alzheimer’s disease

In 2024, Goswami et al. used integrated stress response inhibitor B (ISRIB) to attenuate ER stress-mediated inflammation, neurodegeneration, and cognitive deficits in AD rats by downregulating the expression of ATF4 and CHOP (Table 2 ). 456 This study suggests that ISRIB may serve as a potential drug for the treatment of AD. Rosiglitazone attenuates amyloid β-induced BiP and CHOP-induced ER stress through PPARγ-dependent signaling, thereby protecting human neural stem cells from amyloid β-mediated toxicity, and this study may contribute to the development of new strategies for the treatment of AD. 457 In a study exploring the mechanism of rivastigmine in the treatment of AD, Gupta et al. reported that the levels of ER stress-related markers (GRP78, GADD153, and caspase-12) were significantly inhibited, which could reduce neuronal apoptosis. 458

Parkinson’s disease

Recently, the mechanism of repaglinide in PD therapy was first explored by Motawi et al. 459 By decreasing BiP/ATF6/CHOP and caspase-3 levels, repaglinide attenuates striatal ER stress and apoptosis, suggesting that repaglinide has a protective effect on neuronal cells in PD rats. Pharmacological inhibition of the PERK inhibitor GSK2606414 is neuroprotective against PD caused by PTEN-induced putative kinase 1 (PINK1) mutations, which are caused mainly by the inhibition of defective mitochondrial-activated ER stress, thereby attenuating neurotoxicity. 460

Huntington’s disease

Rosiglitazone significantly increased the survival of neuroblastoma cell lines, which is neuroprotective in mutant Huntington protein-expressing cells. 461 Glucocorticoids can antagonize ER stress-induced apoptosis and prevent HD-mediated neurodegeneration by reducing the expression of eIF2α and CHOP, which highlights the potential of glucocorticoids in the treatment of neurodegenerative diseases. 462

In summary, therapeutic strategies targeting ER stress offer new ideas and possibilities for intervention in neurodegenerative diseases. These drugs not only show promising results in slowing the course of the disease and improving neurological function but also may reduce neuronal cell mortality by modulating the ER stress response. With a deeper understanding of pathogenesis, more effective and safe drugs are expected to be developed in the future.

Metabolic diseases

ER stress plays an important role in the development and progression of several metabolic diseases. When it is dysregulated, it triggers cell death, inflammatory responses, and metabolic diseases. Therefore, therapeutic strategies targeting ER stress are gradually gaining attention, and researchers are developing novel drugs to modulate ER function to improve the pathology of related metabolic diseases.

Insulin resistance

Recently, TUDCA was found to ameliorate high-fat diet-induced obesity and IR by inhibiting ER stress in peripheral tissues, which is a novel application scenario for TUDCA. 463 SalB, an antioxidant that is commonly used to treat cardiovascular diseases, has also been reported to possibly be used to treat IR by improving glucose tolerance. 464 Shi et al. proposed that the mechanism by which SalB ameliorates IR is dependent on ER stress, as evidenced by the attenuation of BiP and CHOP transcription as well as the phosphorylation of PERK and IRE1 in the livers of obese mice. Curcumin, a natural polyphenolic antioxidant compound, inhibits adipose tissue ER stress by dephosphorylating IRE1 and eIF2α and reduces cAMP accumulation by retaining phosphodiesterase 3B induction. 465 The attenuation of ER stress via the cAMP/protein kinase (PK) A pathway, improved insulin sensitivity and reduced lipolysis of fat are all evidence for its use in preventing hepatic IR. Liraglutide and dulaglutide are both glucagon-like peptide 1 (GLP-1) receptor agonists that improve glycemic control by promoting insulin secretion and attenuating ER stress, which is a new finding in the treatment of IR. 466 Liraglutide can improve endothelial cell function by decreasing the levels of eIF2α and IRE1; increasing the expression of genes related to cell differentiation, proliferation, and anti-apoptosis; and inhibiting the expression of genes related to pro-apoptosis, which can effectively reduce IR. 467 Lei et al. reported a significant decrease in IRE1 and ATF6 protein levels in alpha-lipoic acid-treated HepG2 cells, which reduced mitochondrial dysfunction and thus improved IR. 468

Type 2 diabetes

SGLT2 inhibitors, which have been very popular in diabetes research in recent years, can promote ER robustness by preventing ER stress response failure. 469 Canagliflozin (CANA), an SGLT2 inhibitor, restored ER homeostasis by maintaining sarco/ER Ca2+-ATPase activity, restoring the localization of GRP78, and downregulating the expression of eIF2α, ATF4, and CHOP. Recently, Zhang’s team verified that resveratrol, a natural polyphenol, protects insulin secretory function through the ER stress-related PERK pathway, with potential antidiabetic and antiobesity effects. 470 N-acetylcysteine (NAC) has a strong antioxidant effect in vivo, and it can significantly reduce the expression level of CHOP to treat T2D by restoring the function of ER homeostasis. 471 In addition, metformin is one of the most common classical drugs used for the treatment of T2D. Diaz-Morales et al. demonstrated that it modulates ER stress and autophagy in leukocytes from T2D patients, with a particularly pronounced effect on XBP1 and eIF2α. 472 In addition, metformin reversed ER stress, oxidative stress, and endothelium-dependent relaxation injury in mice fed a high-fat diet, thereby protecting endothelial function in obese diabetic mice. 473

Obesity

Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, improves endothelial function by promoting cell proliferation, attenuating the CHOP pathway in ER stress, and reducing high-fat diet-induced endothelial cell dysfunction and apoptosis in the thoracic aorta. 474 Combination therapy with sitagliptin and DA-1241 can achieve better results. Dapagliflozin, another SGLT2 inhibitor, attenuates hepatic oxidative stress and inflammation as well as hepatic and pancreatic ER stress and apoptosis in obese rats, with important implications for treating obesity and metabolic syndrome. 475

Overall, metabolic disease therapeutic drugs that target ER stress provide new clinical hope. These drugs have potential therapeutic effects by attenuating ER stress, enhancing cellular resistance, and improving metabolic pathways. With a deeper understanding of the mechanisms of ER stress, these drugs are expected to become novel therapeutic options for treating metabolic diseases, resulting in improved quality of life and improved patient prognosis.

Autoimmune diseases

Recent studies have shown that ER stress plays an important role in the pathogenesis of autoimmune diseases. The cellular dysfunction and inflammatory response triggered by ER stress may exacerbate the autoimmune response and lead to tissue damage. Therefore, therapeutic strategies targeting ER stress have attracted widespread attention.

Rheumatoid arthritis

Curcumin has anti-inflammatory and immunomodulatory effects in addition to alleviating IR. Zheng et al. reported that curcumin increased the expression of the ER stress-related transcription factors XBP1, ATF6, and CHOP in human CD4+ and Jurkat T cells. 476 This triggering of an excessive ER stress response can induce apoptosis in activated T cells and thus could be a promising treatment for autoimmune diseases. Last year, Chen et al. explored the mechanism of near-infrared photobiomodulation as a novel therapeutic strategy for RA. 477 It attenuates ER stress by decreasing ATF6 expression, thereby reducing the β-amyloid burden and ultimately improving cognitive function. In addition, the E3 ubiquitin ligase synoviolin (SYVN1) is responsible for synoviocyte growth during the development of RA. Earlier studies revealed that the inhibition of SYVN1 expression restored IRE1 protein expression, thereby reversing ER stress-induced apoptosis. 478 Li et al. reported that the inhibition of transient receptor potential melastatin 7 (TRPM7) activates ER stress, which induces FLS apoptosis in RA patients and could be a potential target for the treatment of RA. 479

Multiple sclerosis

Yousuf et al. experimentally reported that elevated expression of ER stress markers was detected in the dorsal root ganglion (DRG) neurons of MS patients and mice. 363 Chronic ER stress can lead to abnormal neuronal function and increased pain sensitivity. The levels of phosphorylated eIF2α, XBP1, and CHOP were significantly decreased in the DRG by 4-PBA treatment. In addition, 4-PBA indirectly reduces the activation of PERK, whose hyperactivation promotes neuronal excitability and pain through the phosphorylation of eIF2α. When PERK phosphorylation was selectively inhibited via AMG-44, the eIF2α signaling pathway was blocked, further validating the role of ER stress in MS pain.

Inflammatory bowel disease

Rees et al. attempted to explore the effects of multiple medications on IBD. 372 The proinflammatory factor TNF-α upregulates the ER stress markers CHOP and GRP78 and enhances the sensitivity of TLR signaling by activating the NF-κB pathway. Azathioprine reduces the ER load in intestinal epithelial cells by inhibiting immune cell activity and decreasing the production of inflammatory factors. Azathioprine inhibits CHOP-mediated apoptosis in intestinal epithelial cells after reducing TNF-α and indirectly reduces XBP1s-driven UPR activation by inhibiting immune activation. In addition, infliximab alleviated ER stress-induced cell death by reducing inflammation, restoring the chaperone function of GRP78, and enhancing the protein-folding capacity of the ER. Ustekinumab can enhance ER protein folding by restoring ATF6 function.

In conclusion, therapeutic agents targeting ER stress for autoimmune diseases have shown promising applications. Although still in the research and clinical trial stages, preliminary results have shown favorable safety and efficacy.

Clinical trials targeting ER stress

We obtained detailed information on 27 clinical trials related to ER stress, including trial design, participant criteria, treatment regimens, and outcomes, as detailed in Table 4 . Table 4 Clinical trials of targeted ER stress NCT Number Applications Study URL Study Status Conditions Intervention method Phases Sample size Study Type Duration NCT03561831 Anesthesia in cancer https://clinicaltrials.gov/study/NCT03561831 COMPLETED Endoplasmic reticulum stress DRUG: Propofol|DRUG: Sevoflurane NA 53 INTERVENTIONAL 1 year NCT04628637 COVID-19 https://clinicaltrials.gov/study/NCT04628637 COMPLETED COVID-19 |Endoplasmic reticulum stress OTHER: Serum protein level analysis NA 144 OBSERVATIONAL 6 months NCT04455256 Recurrent pregnancy loss https://clinicaltrials.gov/study/NCT04455256 COMPLETED Recurrent pregnancy loss|Endoplasmic reticulum stress OTHER: X-box binding protein NA 90 OBSERVATIONAL 4 months NCT04440397 Endometriosis https://clinicaltrials.gov/study/NCT04440397 COMPLETED Endometriosis|Endoplasmic reticulum stress|Endometriosis-related Pain OTHER: XBP1 - endometriosis patients group NA 86 OBSERVATIONAL 5 months NCT02368704 Type 2 diabetes https://clinicaltrials.gov/study/NCT02368704 UNKNOWN Diabetes mellitus, type 2|Endoplasmic reticulum stress OTHER: No intervention NA 40 OBSERVATIONAL 4 days NCT04267809 Symptomatic viral infection https://clinicaltrials.gov/study/NCT04267809 COMPLETED Endoplasmic reticulum stress|Viral infection|Yellow fever DRUG: Metformin hydrochloride|DRUG: Calcium and vitamin D PHASE2 32 INTERVENTIONAL 2 years NCT06621901 Effect of protein on ER stress https://clinicaltrials.gov/study/NCT06621901 NOT_YET_RECRUITING Effect of high protein diet on endoplasmic reticulum stress OTHER: High protein diet|OTHER: Normal protein diet NA 20 INTERVENTIONAL 1 year NCT06025630 Hypertension https://clinicaltrials.gov/study/NCT06025630 RECRUITING Hypertension DRUG: TUDCA|DRUG: Placebo PHASE1|PHASE2 70 INTERVENTIONAL 5 years NCT01211015 Chronic respiratory diseases https://clinicaltrials.gov/study/NCT01211015 UNKNOWN ER stress,|Chronic airway disorders|Lung cancer|Interstitial lung diseases NA 50 OBSERVATIONAL undefined NCT04583631 Adenoid diseases https://clinicaltrials.gov/study/NCT04583631 COMPLETED Adenoiditis acute infective PROCEDURE: Adenoidectomy surgery NA 54 OBSERVATIONAL 9 months NCT04653376 Tonsillar tissue diseases https://clinicaltrials.gov/study/NCT04653376 COMPLETED Tonsillitis|Tonsillar hypertrophy|Immune system diseases PROCEDURE: Tonsillectomy surgery NA 46 OBSERVATIONAL 7 months NCT00771901 Metabolic function https://clinicaltrials.gov/study/NCT00771901 COMPLETED Insulin resistance|Diabetes|Obesity DRUG: tauroursodeoxycholic acid|OTHER: placebo|DRUG: sodium phenylbutyrate NA 101 INTERVENTIONAL 10 months NCT01807910 Nonalcoholic fatty liver disease https://clinicaltrials.gov/study/NCT01807910 WITHDRAWN Obesity|NAFLD DRUG: methyl-D9-choline EARLY_PHASE1 0 INTERVENTIONAL 6 months NCT04001647 Vascular dysfunction https://clinicaltrials.gov/study/NCT04001647 TERMINATED Vasodilation|Arterial stiffness DRUG: Acetylcholine|DRUG: Sodium Nitroprusside|DRUG: Ascorbic Acid EARLY_PHASE1 17 INTERVENTIONAL 1 year NCT02823184 Ph-negative myeloproliferative neoplasms https://clinicaltrials.gov/study/NCT02823184 COMPLETED Polycythemia vera|Essential thrombocythemia BIOLOGICAL: RNA sample of total leukocytes before start of treatment NA 148 OBSERVATIONAL 2 years NCT02302326 Physiopathology of polycystic ovary syndrome https://clinicaltrials.gov/study/NCT02302326 COMPLETED Polycystic ovary syndrome DRUG: Metformin|DIETARY_SUPPLEMENT: Myo-inositol + folic acid NA 50 INTERVENTIONAL 11 months NCT03722979 Extracorporeal circulation in humans https://clinicaltrials.gov/study/NCT03722979 UNKNOWN Cardiac surgery PROCEDURE: Cardiac surgery NA 53 INTERVENTIONAL 7 months NCT03331432 Vascular function https://clinicaltrials.gov/study/NCT03331432 COMPLETED Type 2 diabetes mellitus DIETARY_SUPPLEMENT: Tauroursodeoxycholic acid|DIETARY_SUPPLEMENT: Placebo NA 8 INTERVENTIONAL 2 years NCT04041232 Achromatopsia https://clinicaltrials.gov/study/NCT04041232 NOT_YET_RECRUITING ACHROMATOPSIA 7|Achromatopsia DRUG: PBA EARLY_PHASE1 2 INTERVENTIONAL 2 days NCT01877551 Insulin resistance https://clinicaltrials.gov/study/NCT01877551 COMPLETED HIV related insulin resistance|Protease inhibitor related insulin resistance|Endoplasmic reticulum stress DRUG: Tauroursodeoxycholic acid|OTHER: Placebo tablet NA 27 INTERVENTIONAL 9 months NCT02218619 Type 1 diabetes https://clinicaltrials.gov/study/NCT02218619 UNKNOWN Type 1 diabetes DRUG: Tauroursodeoxycholic Acid (TUDCA)|DRUG: Sugar Pill (placebo) PHASE2 20 INTERVENTIONAL 2 months NCT02841553 Wolfram syndrome https://clinicaltrials.gov/study/NCT02841553 RECRUITING Wolfram syndrome|Diabetes mellitus|Optic nerve atrophy|Deafness|Diabetes insipidus|Ataxia NA 300 OBSERVATIONAL 9 months NCT03798977 Melanoma https://clinicaltrials.gov/study/NCT03798977 COMPLETED Melanoma NA 20 OBSERVATIONAL 3 years NCT03462940 Type 2 DM https://clinicaltrials.gov/study/NCT03462940 TERMINATED Diabetes mellitus, type 2|Insulin response|Endothelial dysfunction DIETARY_SUPPLEMENT: tauroursodeoxycholic acid NA 2 INTERVENTIONAL 10 months NCT02829268 Wolfram syndrome https://clinicaltrials.gov/study/NCT02829268 COMPLETED Wolfram syndrome|Diabetes mellitus|Optic nerve atrophy|Ataxia DRUG: dantrolene sodium PHASE1|PHASE2 21 INTERVENTIONAL 2 months NCT06660784 Diaphragm dysfunction https://clinicaltrials.gov/study/NCT06660784 ACTIVE_NOT_RECRUITING Tracheal intubation|Extracorporeal membrane oxygenation|Nitric oxide|Ventilator-induced diaphragmatic dysfunction DRUG: nitric oxide NA 80 OBSERVATIONAL 2 years NCT01056497 Impairment of glucose-stimulated insulin secretion https://clinicaltrials.gov/study/NCT01056497 COMPLETED Type 2 diabetes|Prediabetes DRUG: alpha lipoic acid PHASE4 15 INTERVENTIONAL 4 months NCT04041232 PBA use for treatment https://clinicaltrials.gov/study/NCT04041232 NOT_YET_RECRUITING ACHROMATOPSIA 7|Achromatopsia DRUG: PBA EARLY_PHASE1 2 INTERVENTIONAL 3 days NCT04122586 Intestinal mucosal barrier of IBS-D https://clinicaltrials.gov/study/NCT04122586 UNKNOWN IBS (irritable bowel syndrome) DRUG: Tongxieyaofang (granule) NA 60 INTERVENTIONAL 3 years NCT05027594 Multiple myeloma https://clinicaltrials.gov/study/NCT05027594 TERMINATED Multiple myeloma DRUG: NMS-03597812|DRUG: NMS-03597812 + dexamethasone PHASE1 5 INTERVENTIONAL 2 years

TUDCA and PBA are common modulators of the ER stress pathway. These two agents were used in a clinical trial ( NCT00771901 ) to induce a decrease in the ER stress response to improve insulin action and hepatic lipid metabolism in obese patients with IR and hyperlipidemia. 480 Researchers have conducted a 4-week randomized controlled trial in obese subjects to assess adipose tissue insulin signaling, ER stress, and inflammation by evaluating adipose tissue biopsy tissue both in vivo and ex vivo. TUDCA was administered at 1750 mg per day for four weeks: seven capsules per day, two for breakfast, two for lunch, and three for dinner. 20 grams of PBA per day for four weeks. The results of the trial after four weeks revealed that treatment with TUDCA increased insulin sensitivity in the liver and muscle by approximately 30%, but no effects of TUDCA on adipose tissue insulin sensitivity or ER stress were detected. Although treatment of obese mice with TUDCA reduced ER stress in the liver and adipose tissue, the association may not be significant in the population. In addition, liver sensitivity to insulin and VLDL-triglyceride (TG) concentrations were increased in PBA-treated patients.

Furthermore, TUDCA was explored in a clinical trial ( NCT01877551 ) to improve insulin action in HIV-infected patients. Researchers improved insulin sensitivity in subjects with protease inhibitor-associated IR by determining whether and how TUDCA improves insulin sensitivity through ER stress. Body composition analysis was performed on 48 HIV-infected, IR/prediabetic subjects via a DEXA machine to measure liver fat via MRI. Patients will take 1.75 grams of TUDCA once daily for 30 days. The control group will take the same placebo tablets as the treatment group but without TUDCA. Once a day for 30 days. Each subject’s fat content, relative amount of fat in the liver, and liver function will be measured daily before and after treatment with TUDCA or placebo. The results revealed a significant reduction in glucose uptake and the relative amount of fat in the liver.

Dantrolene sodium is an acetylenic urea derivative skeletal muscle relaxant whose core target of action is ryanodine receptors (RyRs), which are located in the ER membrane and are responsible for regulating the release of calcium ions from the ER to the cytoplasm. 481 It was used to treat Wolfram syndrome in a recent clinical trial ( NCT02829268 ). 482 Wolfram syndrome is a rare, autosomal recessive disorder caused by mutations in the WFS1 gene. The protein encoded by WFS1 is localized in the ER membrane and is involved in the regulation of ER calcium homeostasis and the stress response. WFS1 dysfunction leads to depletion of the ER calcium pool, triggering persistent ER stress and ultimately leading to the apoptosis of pancreatic β-cells and neurons. Studies have shown that the activation of calcium-dependent proteases accelerates cell death in WFS1-deficient cells and that ER calcium imbalance is a central mechanism in this process. 483 The trial included a 56-day screening period, a 6-month treatment period (with an optional extension period of up to 24 months), and a 4-week safety follow-up period. By blocking RyR channels, dantrolene sodium reduces the passive leakage of calcium from the ER and increases storage capacity. Preclinical studies have shown that in WFS1-deficient mice and induced pluripotent stem cell (iPSC) models, dantrolene sodium significantly increases intra-ER calcium levels and decreases calpain activity, thereby protecting cells from apoptosis. To test the therapeutic effect of dantrolene sodium, researchers determined the effect of dantrolene sodium on remaining beta-cell functions via a mixed-meal tolerance test and monitored baseline C-peptide levels, blood glucose levels, proinsulin/C-peptide ratios, hemoglobin A1c levels, and urine glucose levels. In addition, the researchers assessed the effect of dantrolene sodium on visual functions through LogMar scores and questionnaires and evaluated the efficacy of dantrolene sodium on neurological functions via the Wolfram Unified Rating Scale (WURS) and standard neurological assessments. The results revealed no significant improvement in beta-cell function at the end of the six-month treatment, but there was a significant correlation between baseline beta-cell function and changes in beta-cell reactivity. Furthermore, tolerance ranges of 0.5 mg/kg/d to 2 mg/kg/d for oral dantrolene sodium in children and 50 mg/d to 100 mg/d for oral dantrolene sodium in adults were determined. Overall, Dantrolene sodium was well tolerated in patients with Wolfram syndrome.

An analysis of the ClinicalTrials.gov database revealed that these studies focused mainly on cancer treatment and metabolic diseases, aiming to explore how to improve the prognosis of diseases and patients’ quality of life by modulating the ER stress response.

Novel drugs for treating ER stress

As research into the molecular mechanisms of ER stress continues to evolve, the need for innovative therapeutic approaches has become increasingly apparent, prompting scientists to explore targeted interventions. Emerging drugs aim to enhance the protective mechanisms of cells against ER stress or selectively eliminate damaged cells, offering a promising avenue for treating conditions previously deemed difficult to manage. These advancements represent a significant shift in the therapeutic landscape, highlighting the potential for tailored treatments that address the underlying causes of ER stress-related diseases.

Cancer vaccines

A cancer vaccine uses tumor antigens to induce specific antitumor effects through active immunity, stimulating the immune system to treat or prevent tumor recurrence as a form of active immunotherapy. It amplifies the responsiveness of tumor-specific T cells, usually through active immunity, and has long been regarded as a vital tool for effective cancer immunotherapy. 484 In 2010, Boozari et al. reported that PIs disrupted the UPR and enhanced ER stress-induced apoptosis, leading to the proposal of virotherapy as an antitumor vaccine. 485 The ideal in situ vaccine strategy induces tumor ICD, effectively activating an immune response against antigens from dead or dying tumor cells. Recently, Liu et al. developed Par-ICG-Lipo, a cancer vaccine, by loading indocyanine green (ICG) into liposomes and modifying its surface with a peptide targeting the ER with pardaxin. 40 Par-ICG-Lipo-induced ER-targeted photodynamic therapy (PDT) promotes tumor antigen release in vivo, stimulating a strong antitumor immune response. 486 Specifically, significant increases in both CD8+ and CD4+ T cells suggest that in situ tumor vaccines effectively promote DC maturation and immune system activation. While both ICG-Lipo and Par-ICG-Lipo showed antitumor effects under laser irradiation, Par-ICG-Lipo was more potent. This innovative in situ tumor vaccine represents a clinically viable approach for cancer treatment. SA-Cbl, another ICD inducer, is also being explored for cancer vaccine development. 487 It was developed by conjugating chloramphenicol (Cbl) with salicylaldehyde (SA), which precisely targets the ER-activated UPR pathway and promotes DC maturation. These findings indicate that SA-Cbl has superior anticancer immune effects compared with those of standard chemotherapies, such as doxorubicin.

The latest cancer vaccines targeting ER stress, called photoactivatable TLR7/8 antagonists (PNAs), rely on PDT-generated ROS to induce ICD, resulting in tumor antigens and, finally, the activation of T lymphocytes for tumor killing (Table 2 ). 488 This vaccine has shown efficacy in several tumor models, especially in in situ breast cancer models. Treatment with PNA and infrared light reduced the primary tumor size in cured mice. Recent studies have highlighted oncolytic viruses such as swine pseudorabies virus vaccines, which induce eIF2α expression in tumor cells, activating ER stress to kill cancer cells (Table 2 ). 489 Similarly, tumor-derived extracellular vesicles are being explored as cancer vaccines. Extracellular vesicles can induce ER stress in tumor cells, leading to the effective activation of DCs and the enhancement of antitumor immune responses. 490 The addition of immune adjuvants may enhance these novel tumor vaccines. Despite their development, cancer vaccines are still in the early stages compared with conventional treatments. Their safety requires further validation before widespread clinical use can be achieved.

Fluorescent probes

In recent years, fluorescent probes have been identified as novel strategies for imaging tumors and guiding therapies. Fluorescent probes that target the ER can not only identify the type of ER stress-producing cells but also quantify the dynamics of the ER stress response. ER-BnXPI, an ER-targeted near-infrared fluorescent probe, showed excellent subcellular localization to the ER and successfully distinguished tumor tissue from paracancerous tissue. 491 Similarly, the ER-localized response molecules (ERMs) developed by Fujisawa et al. achieved spontaneous localization in the ER of cells and even selectively labeled ER-associated proteins via affinity and imaging tags, which supported the quantitative analysis of the extent of ER-associated protein-induced ER stress responses. 492 Wang et al. synthesized a unique near-infrared fluorophore, IR-34, which can selectively trigger ER stress in tumors. 493 Experiments have shown that IR-34 can significantly inhibit tumor growth and recurrence without significant toxicity. TPA-DHPy, a state-of-the-art photoactivatable fluorescent probe, can be absorbed by cancer cells and gradually light up lipid droplets and the ER during photoactivation. In addition, it can further disrupt the function of the ER under prolonged irradiation and significantly inhibit tumor growth through photodynamic therapy. 494 In addition to fluorescent probe technology, Man et al. combined it with gene coding technology to synthesize CLP-TMR, which can reconstruct the molecular location of ER morphology via direct stochastic optical reconstruction microscopy imaging. 495 These studies provide useful insights for the design of a new generation of therapeutic agents targeting ER stress, which could help realize imaging-guided precision cancer therapy.

Nanogel drugs

The development of nanomedicine platforms offers the possibility to address the shortcomings of conventional drugs, but developing nanomedicines and thus achieving efficient treatment of tumors has been a challenge. Grandhi et al. synthesized a novel aminoglycoside-derived hydrogel, Amikagel, which can promote dormancy in bladder cancer cells (Table 2 ). It induces ER stress by inhibiting targets in the cellular protein production machinery, and in addition, nanoparticle-mediated calcium delivery significantly accelerates ER stress-mediated death in the three-dimensional dormant TME. 496 Recently, ER and mitochondria dual-targeting nanoparticles (EMT-NPs) have been designed as alternatives to conventional drugs for cancer treatment (Table 2 ). 497 EMT-NPs synergistically induce ER stress and mitochondrial dysfunction in tumor cells and induce calcium ion overload in mitochondria by increasing the expression of ER stress-related proteins (IRE1 and CHOP), which further exacerbates apoptosis in cancer cells. The intelligent redox-responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and the chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) developed by Zhang et al. represent the latest nanomedicine targeting ER stress (Table 2 ). 498 Toy released from Au/Toy@G3 NGs promotes cancer apoptosis via ER stress and causes immunogenic cell death in mature DCs. In experiments on mouse models of pancreatic tumors, the combination of Au/Toy@G3 NGs with ultrasound-targeted microbubble destruction and anti-PD-L1 had the best tumor suppression effect in combination therapy, enabling effective chemoimmunotherapy. In conclusion, these nanogel strategies with targeted ER stress-associated functions offer unlimited possibilities for cancer therapeutics in precision nanomedicine.

Conclusions and perspectives

Conclusions

ER stress is thought to be an adaptive mechanism that maintains ER homeostasis by increasing protein-folding capacity and degrading misfolded proteins. The dual role of ER stress has been reported in detail; it promotes cell survival through the UPR at the early stage and triggers apoptosis under prolonged stress. 499 Under transient ER stress, the UPR is activated through three major sensors and works synergistically to reduce stress. Sustained ER stress overwhelms adaptive mechanisms and shifts the UPR toward apoptosis. Chen et al. reported that Cab45S can inhibit the IRE1-JNK pathway by stabilizing BiP/GRP78, which plays an important role in the bidirectional regulation of ER stress and provides a key node for balancing cell survival and apoptosis. 500 Research has identified persistent ER stress as a new hallmark of disease progression. Genetic variants, hypoxia, metabolic abnormalities, and therapeutic agents can lead to ER stress, disrupting protein-folding homeostasis in normal tissue cells. This uncontrolled ER stress response promotes disease progression, such as the proliferation and metastasis of malignant cells, and increases their survival and adaptability.

On the basis of these findings, therapeutic options targeting the three classical downstream pathways of the UPR and related proteins are becoming a hot topic in the fight against tumors, cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. In particular, the popularity of novel therapeutic technologies, such as cancer vaccines, has recently accelerated the development of drugs targeting the UPR signaling pathway. Successful drug utilization involves multiple levels of complexity. Three major pathways of the UPR coordinate cellular stress responses, in which complex cross-regulatory and feedback mechanisms exist. The UPR constitutes a complex regulatory network involving oxidative stress, autophagy, and apoptosis. The diversity of interactions and regulatory mechanisms of these pathways increases the difficulty of drug development. IRE1 activation promotes adaptive responses through XBP1 splicing, but its overactivation may induce apoptosis through the JNK pathway 52 ; PERK selectively activates ATF4 to increase antioxidant capacity while inhibiting global translation, but sustained activation triggers cell death via CHOP. 59 This duality requires that drugs must precisely modulate target activity within a specific threshold or that they may switch from therapeutic to toxic. This makes drug design highly precise and difficult to generalize, increasing the difficulty of drug development. In addition, significant differences between animal models and the clinic are also a problem. TUDCA improved insulin resistance in animal models, but the results of clinical trials are not significant, and improvements are still needed. 480 We fully discuss the differences in the triggering mechanisms and modes of action of ER stress in a wide range of diseases, including cancer, cardiovascular disease, neurodegenerative disease, metabolic disease, and autoimmune disease. This also suggests the need to develop highly specific targeted drugs to improve personalized therapeutic capabilities.

Challenges

Despite their various advantages, their safety remains to be further demonstrated, and many mechanisms remain to be explored (Fig. 7 ). Fig. 7 Therapeutic challenges and emerging strategies. This figure highlights unresolved mechanisms and translational barriers in the targeting of ER stress for therapeutic intervention. Major challenges include the lack of clarity in the characterization of ATF6 signaling. ATF6 signaling in immune cells and its spatial regulation within the TME remain poorly characterized. There is a lack of mechanistic insights into ATF6-mediated crosstalk between ER stress and immune evasion. Current research is limited by overreliance on single-disease models. Predominant reliance on isolated disease models fails to recapitulate ER stress dynamics in comorbid conditions. Inadequate representation of multiorgan interactions and systemic pathological cascades. The barriers to clinical translation remain significant. The complexity of ER stress-related signaling networks complicates target identification and validation. Scarcity of large-scale clinical trials and standardized biomarkers for assessing treatment efficacy. Differences between species give rise to safety concerns for clinical administration. Divergent drug responses between animal models and human physiology limit predictive accuracy. Potential off-target effects of ER stress modulation on normal cellular homeostasis require rigorous evaluation. Future strategies emphasize cross-disease integration through multiomics and systems biology. Precision therapeutics could leverage genomic/proteomic profiling for patient-specific UPR pathway modulation. Innovations such as nanogel-based drug carriers and ER stress-responsive vaccines may enhance spatiotemporal control and synergize with immunotherapy. Advanced models, including CRISPR-edited organoids, multidisease murine systems, and organ-on-chip platforms, aim to replicate human pathophysiology and tumor-immune interplay

First, in cancer research, aberrant activation of ER stress sensors and their upstream and downstream signaling pathways has become a key regulator of tumor growth and metastasis, as well as the response to chemotherapy, targeted therapy, and immunotherapy. Findings have consistently shown that rational control of the ER stress response can significantly inhibit tumor progression by promoting malignant apoptosis and enhancing the immune response. Therefore, a deeper understanding of the precise molecular mechanisms by which ER stress affects immune cell function may greatly improve the efficacy of cancer immunotherapy in the clinical setting. Although breakthroughs in IRE1-, PERK-, and BiP-based immunosuppression studies have been reported in recent years, information on the upstream and downstream modalities of ATF6 regulation is lacking. The detailed mechanisms by which ATF6 functions in T and B cells have not been fully elucidated. Exploring the impact of ATF6 on immune cells is crucial. Furthermore, the impact of immune cell spatial localization within tumors on the ER stress response remains to be demonstrated. While single-cell omics techniques have decoded intratumor heterogeneity, they do not preserve the spatial coordinates of cells. Spatial omics, which provides precise cellular and molecular localization information, is revolutionizing our understanding of the cancer environment. The application of spatial histology techniques to explore the effects of ER stress on immune cells in the TME has the potential to provide innovative solutions for designing precision medicine strategies.

Second, most studies have focused on single-disease models and lack a comprehensive analysis of multiple disease interactions. This limitation not only affects our understanding of ER stress mechanisms but also restricts the clinical application value of the findings, especially when multiple disease pathologic states are involved. Single-disease models are usually created under laboratory conditions for specific disease states, such as T2D, AD, or HF. These studies often provide insight into the mechanism of action of ER stress in the context of a specific disease. However, this approach ignores the reality that many patients have multiple diseases simultaneously. For example, metabolic syndrome, as a complex pathological state, involves multiple aspects of obesity, diabetes, hypertension, and dyslipidemia. In the context of metabolic syndrome, ER stress may not only be a consequence of disease occurrence but also interact with different pathologic states. For example, IR and adipocyte dysfunction may lead to increased ER stress, exacerbating diabetes and cardiovascular disease. However, most current studies have neglected these interactions, resulting in our inability to fully understand the true role of ER stress in the context of complex diseases. In addition, combining multidimensional data from genomics, transcriptomics, proteomics, and metabolomics to construct comprehensive models of ER stress-related diseases can lead to a better understanding of the molecular mechanisms of complex diseases.

Third, by monitoring the extent of ER stress and the corresponding biomarkers, it is possible to understand the regulation of the intracellular environment by treatment, which can inform the assessment of efficacy in clinical trials. However, we also found a need for clinical trials on ER stress, one of the major reasons being that ER stress involves multiple signaling pathways and regulatory factors and that its molecular mechanisms are complex and still need to be fully understood. This complexity adds to the technical challenges of applying it to clinical trials. In particular, assessing the activity and impact of ER stress requires the use of specific experimental techniques and biomarkers, which increases the difficulty of implementing appropriate clinical trials. Moreover, the translation of ER stress research into clinical trials is in its early stages and requires further in-depth research and validation. Existing clinical studies related to ER stress are particularly rare. In addition, established clinical studies of ER stress often rely on small experimental or clinical samples, which may result in findings that are not statistically significant or lack generalizability. ER stress research necessitates multidisciplinary collaboration, spanning the fields of cell biology, immunology, and clinical medicine. Therefore, when relevant clinical trials are conducted, expertise and resources from different fields must be integrated to ensure the scientific validity and feasibility of the study design.

Finally, current research suggests that there may be differences in the response to and tolerance of different individuals to ER stress, which poses a challenge for clinical application and individualized therapy. Although many ER stress-related studies rely on animal models (e.g., mouse models), the physiological states and stress responses of these animal models differ from those of humans, particularly in terms of drug response, the immune system, and organ specificity. The therapeutic effects of drugs targeting ER stress observed in animal models may not be fully replicated in clinical human cases. Furthermore, ER stress interventions and modulation may affect normal cellular functions. Consequently, in-depth studies are needed to ensure treatment safety and efficacy.

Outlooks

In future studies, the following aspects should be emphasized (Fig. 7 ).

First, comprehensive cross-disease modeling studies are needed to better understand the role of ER stress in different pathological states. Such studies can reveal the interactions between ER stress and other cellular stress pathways and help us understand the complexity of the disease.

Second, the personalization of targeted therapy is important. Future therapeutic strategies should consider patients’ genetic backgrounds and specific pathological states to develop personalized, targeted drugs. Genomics and proteomics research can identify potentially effective therapeutic targets in specific patient populations. In addition, there is a need for continued focus and development of novel drugs that are more effective in modulating ER stress and have fewer toxic side effects. This is where the link between basic research and clinical applications needs to be strengthened to facilitate the translation of research results.

Third, fluorescent probes, nanogel drugs, and tumor vaccines targeting ER stress are still in the early stages of development. The fluorescent probe can accurately identify the type of ER stress-producing cells and precisely trigger ER stress in tumor cells to accelerate their apoptosis. Compared with conventional treatments, nanogel drugs can deliver the encapsulated drug to the lesion site and reduce the toxic response to normal tissues. In addition, tumor vaccines, emerging personalized immunotherapies that autonomously stimulate the immune system for treatment, may lead to long-lasting therapeutic effects and protection against future tumor recurrence. Making ER stress tumor vaccines available for clinical use requires rigorous clinical trials to evaluate their safety, efficacy, and applicability, which is one of the important tasks ahead.

Finally, complex animal models, such as gene-edited animals, conditionally transgenic animals, and multiple disease models, are essential. The success of animal experiments does not always translate into clinical efficacy, mainly because of the complex environment in vivo and the differences between different organisms. Therefore, there is no substitute for increasingly complex animal experiments.

In conclusion, ER stress plays an important role in the occurrence and development of a variety of diseases, and in-depth studies of its mechanism have provided new ideas for targeted therapy. Although current studies have progressed, many challenges and limitations still exist. Future development should focus on the establishment of multiple disease models, the exploration of personalized therapy, the development of novel drugs, and improvements in the design of clinical studies. These efforts are anticipated to lead to significant breakthroughs in targeted ER stress research and treatment, offering new opportunities for the prevention and treatment of related diseases.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Siyu Wei, Nan Zhang, Hao Zhang, Zigui Chen, Shuyu Li

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NO. 82303610, 82503442), the Chongqing Medical Youth Top Talent Program (NO. YXQN202558), the Chongqing Youth Innovation Talent Project (NO. CSTB2025YITP-QCRCX0096), the Science and Technology innovation Program of Hunan Province (NO. 2023RC3074), the Beijing Xisike Clinical Oncology Research Foundation (NO. Y-Gilead2024-PT-0070), the Science Foundation of the AMHT Group (NO. 2025YK06), the Medical Artificial Intelligence Fund of Tongji Hospital (NO. 2201103705), and the Science Foundation of Hunan Aerospace Hospital (NO. 2025YJ01).

Author contributions

Quan Cheng, Peng Luo, and Zhiwei Xia conceived and designed the study. Siyu Wei, Nan Zhang, Hao Zhang, Zigui Chen, and Shuyu Li drafted the manuscript. Zaoqu Liu, Wantao Wu, Quan Cheng, Peng Luo, Zhiwei Xia, Siyu Wei, Nan Zhang, Hao Zhang, Zigui Chen, and Shuyu Li revised the manuscript. Quan Cheng, Hao Zhang, Wantao Wu, and Zhiwei Xỉa provided funding support. All the authors have read and approved the article.

Competing interests

The authors declare no competing interests.

References

1. Lin JH Walter P Yen TS Endoplasmic reticulum stress in disease pathogenesis Annu. Rev. Pathol. 2008 3 399 425 10.1146/annurev.pathmechdis.3.121806.151434 18039139 PMC3653419 Lin, J. H., Walter, P. & Yen, T. S. Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. 3 , 399–425 (2008). 18039139 10.1146/annurev.pathmechdis.3.121806.151434 PMC3653419

2. Fagone P Jackowski S Membrane phospholipid synthesis and endoplasmic reticulum function J. Lipid Res. 2009 50 S311 S316 10.1194/jlr.R800049-JLR200 18952570 PMC2674712 Fagone, P. & Jackowski, S. Membrane phospholipid synthesis and endoplasmic reticulum function. J. Lipid Res. 50 , S311–S316 (2009). 18952570 10.1194/jlr.R800049-JLR200 PMC2674712

3. Hetz C Zhang K Kaufman RJ Mechanisms, regulation and functions of the unfolded protein response Nat. Rev. Mol. Cell Biol. 2020 21 421 438 10.1038/s41580-020-0250-z 32457508 PMC8867924 Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21 , 421–438 (2020). 32457508 10.1038/s41580-020-0250-z PMC8867924

4. Hebert DN Molinari M In and out of the ER: protein folding, quality control, degradation, and related human diseases Physiol. Rev. 2007 87 1377 1408 10.1152/physrev.00050.2006 17928587 Hebert, D. N. & Molinari, M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol. Rev. 87 , 1377–1408 (2007). 17928587 10.1152/physrev.00050.2006

5. Hetz C The unfolded protein response: controlling cell fate decisions under ER stress and beyond Nat. Rev. Mol. Cell Biol. 2012 13 89 102 10.1038/nrm3270 22251901 Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13 , 89–102 (2012). 22251901 10.1038/nrm3270

6. Liu Y Ye Y Proteostasis regulation at the endoplasmic reticulum: a new perturbation site for targeted cancer therapy Cell Res. 2011 21 867 883 10.1038/cr.2011.75 21537343 PMC3203708 Liu, Y. & Ye, Y. Proteostasis regulation at the endoplasmic reticulum: a new perturbation site for targeted cancer therapy. Cell Res. 21 , 867–883 (2011). 21537343 10.1038/cr.2011.75 PMC3203708

7. Sharma P Hu-Lieskovan S Wargo JA Ribas A Primary, adaptive, and acquired resistance to cancer immunotherapy Cell 2017 168 707 723 10.1016/j.cell.2017.01.017 28187290 PMC5391692 Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168 , 707–723 (2017). 28187290 10.1016/j.cell.2017.01.017 PMC5391692

8. Lee GE Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death Exp. Mol. Med. 2024 56 686 699 10.1038/s12276-024-01195-1 38480902 PMC10985101 Lee, G. E. et al. Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death. Exp. Mol. Med. 56 , 686–699 (2024). 38480902 10.1038/s12276-024-01195-1 PMC10985101

9. Unal B Targeting IRE1alpha reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer Nat. Commun. 2024 15 8895 10.1038/s41467-024-53039-1 39406723 PMC11480464 Unal, B. et al. Targeting IRE1alpha reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. Nat. Commun. 15 , 8895 (2024). 39406723 10.1038/s41467-024-53039-1 PMC11480464

10. Ren J Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases Nat. Rev. Cardiol. 2021 18 499 521 10.1038/s41569-021-00511-w 33619348 Ren, J. et al. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat. Rev. Cardiol. 18 , 499–521 (2021). 33619348 10.1038/s41569-021-00511-w

11. Lindholm D Wootz H Korhonen L ER stress and neurodegenerative diseases Cell Death Differ. 2006 13 385 392 10.1038/sj.cdd.4401778 16397584 Lindholm, D., Wootz, H. & Korhonen, L. ER stress and neurodegenerative diseases. Cell Death Differ. 13 , 385–392 (2006). 16397584 10.1038/sj.cdd.4401778

12. Sarvani C Sireesh D Ramkumar KM Unraveling the role of ER stress inhibitors in the context of metabolic diseases Pharm. Res. 2017 119 412 421 10.1016/j.phrs.2017.02.018 28237513 Sarvani, C., Sireesh, D. & Ramkumar, K. M. Unraveling the role of ER stress inhibitors in the context of metabolic diseases. Pharm. Res. 119 , 412–421 (2017). 10.1016/j.phrs.2017.02.018 28237513

13. Junjappa RP IRE1alpha implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases Front. Immunol. 2018 9 1289 10.3389/fimmu.2018.01289 29928282 PMC5997832 Junjappa, R. P. et al. IRE1alpha implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases. Front. Immunol. 9 , 1289 (2018). 29928282 10.3389/fimmu.2018.01289 PMC5997832

14. Shiu RP Pouyssegur J Pastan I Glucose depletion accounts for the induction of two transformation-sensitive membrane proteinsin Rous sarcoma virus-transformed chick embryo fibroblasts Proc. Natl. Acad. Sci. USA 1977 74 3840 3844 10.1073/pnas.74.9.3840 198809 PMC431753 Shiu, R. P., Pouyssegur, J. & Pastan, I. Glucose depletion accounts for the induction of two transformation-sensitive membrane proteinsin Rous sarcoma virus-transformed chick embryo fibroblasts. Proc. Natl. Acad. Sci. USA 74 , 3840–3844 (1977). 198809 10.1073/pnas.74.9.3840 PMC431753

15. Dorner AJ Wasley LC Kaufman RJ Increased synthesis of secreted proteins induces expression of glucose-regulated proteins in butyrate-treated Chinese hamster ovary cells J. Biol. Chem. 1989 264 20602 20607 10.1016/S0021-9258(19)47105-6 2511206 Dorner, A. J., Wasley, L. C. & Kaufman, R. J. Increased synthesis of secreted proteins induces expression of glucose-regulated proteins in butyrate-treated Chinese hamster ovary cells. J. Biol. Chem. 264 , 20602–20607 (1989). 2511206

16. Melnick J Aviel S Argon Y The endoplasmic reticulum stress protein GRP94, in addition to BiP, associates with unassembled immunoglobulin chains J. Biol. Chem. 1992 267 21303 21306 10.1016/S0021-9258(19)36608-6 1400441 Melnick, J., Aviel, S. & Argon, Y. The endoplasmic reticulum stress protein GRP94, in addition to BiP, associates with unassembled immunoglobulin chains. J. Biol. Chem. 267 , 21303–21306 (1992). 1400441

17. Yoshida H Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors J. Biol. Chem. 1998 273 33741 33749 10.1074/jbc.273.50.33741 9837962 Yoshida, H. et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem. 273 , 33741–33749 (1998). 9837962 10.1074/jbc.273.50.33741

18. Wang XZ Cloning of mammalian Ire1 reveals diversity in the ER stress responses EMBO J. 1998 17 5708 5717 10.1093/emboj/17.19.5708 9755171 PMC1170899 Wang, X. Z. et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17 , 5708–5717 (1998). 9755171 10.1093/emboj/17.19.5708 PMC1170899

19. Harding HP Zhang Y Ron D Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase Nature 1999 397 271 274 10.1038/16729 9930704 Harding, H. P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397 , 271–274 (1999). 9930704 10.1038/16729

20. Katayama T Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response Nat. Cell Biol. 1999 1 479 485 10.1038/70265 10587643 Katayama, T. et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat. Cell Biol. 1 , 479–485 (1999). 10587643 10.1038/70265

21. Segawa T Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells Oncogene 2002 21 8749 8758 10.1038/sj.onc.1205992 12483528 Segawa, T. et al. Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene 21 , 8749–8758 (2002). 12483528 10.1038/sj.onc.1205992

22. Ozcan U Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes Science 2004 306 457 461 10.1126/science.1103160 15486293 Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306 , 457–461 (2004). 15486293 10.1126/science.1103160

23. Okada K Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis Circulation 2004 110 705 712 10.1161/01.CIR.0000137836.95625.D4 15289376 Okada, K. et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110 , 705–712 (2004). 15289376 10.1161/01.CIR.0000137836.95625.D4

24. Bodman-Smith MD Antibody response to the human stress protein BiP in rheumatoid arthritis Rheumatology 2004 43 1283 1287 10.1093/rheumatology/keh312 15252212 Bodman-Smith, M. D. et al. Antibody response to the human stress protein BiP in rheumatoid arthritis. Rheumatology 43 , 1283–1287 (2004). 15252212 10.1093/rheumatology/keh312

25. Inden M Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone J. Neurochem. 2007 101 1491 1504 10.1111/j.1471-4159.2006.04440.x 17459145 Inden, M. et al. Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J. Neurochem. 101 , 1491–1504 (2007). 17459145 10.1111/j.1471-4159.2006.04440.x

26. Lin JH IRE1 signaling affects cell fate during the unfolded protein response Science 2007 318 944 949 10.1126/science.1146361 17991856 PMC3670588 Lin, J. H. et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 318 , 944–949 (2007). 17991856 10.1126/science.1146361 PMC3670588

27. Zhang X Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity Cell 2008 135 61 73 10.1016/j.cell.2008.07.043 18854155 PMC2586330 Zhang, X. et al. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135 , 61–73 (2008). 18854155 10.1016/j.cell.2008.07.043 PMC2586330

28. Ozcan L Endoplasmic reticulum stress plays a central role in development of leptin resistance Cell Metab. 2009 9 35 51 10.1016/j.cmet.2008.12.004 19117545 Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9 , 35–51 (2009). 19117545 10.1016/j.cmet.2008.12.004

29. Rouschop KM The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5 J. Clin. Invest. 2010 120 127 141 10.1172/JCI40027 20038797 PMC2798689 Rouschop, K. M. et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 120 , 127–141 (2010). 20038797 10.1172/JCI40027 PMC2798689

30. Papandreou I Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma Blood 2011 117 1311 1314 10.1182/blood-2010-08-303099 21081713 PMC3056474 Papandreou, I. et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 117 , 1311–1314 (2011). 21081713 10.1182/blood-2010-08-303099 PMC3056474

31. Mimura N Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma Blood 2012 119 5772 5781 10.1182/blood-2011-07-366633 22538852 PMC3382937 Mimura, N. et al. Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood 119 , 5772–5781 (2012). 22538852 10.1182/blood-2011-07-366633 PMC3382937

32. Cross BC The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule Proc. Natl. Acad. Sci. USA 2012 109 E869 E878 10.1073/pnas.1115623109 22315414 PMC3326519 Cross, B. C. et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. USA 109 , E869–E878 (2012). 22315414 10.1073/pnas.1115623109 PMC3326519

33. Axten, J. M. et al. Discovery of 7-methyl-5-(1-[3-(trifluoromethyl)phenyl]acetyl-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 55, 7193–7207 (2012). . 10.1021/jm300713s 22827572

34. Ghosh R Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress Cell 2014 158 534 548 10.1016/j.cell.2014.07.002 25018104 PMC4244221 Ghosh, R. et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158 , 534–548 (2014). 25018104 10.1016/j.cell.2014.07.002 PMC4244221

35. Tang CH Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival J. Clin. Invest. 2014 124 2585 2598 10.1172/JCI73448 24812669 PMC4038575 Tang, C. H. et al. Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J. Clin. Invest. 124 , 2585–2598 (2014). 24812669 10.1172/JCI73448 PMC4038575

36. Mijit M Activation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment Front. Med. 2023 10 1146115 10.3389/fmed.2023.1146115 PMC10174294 37181357 Mijit, M. et al. Activation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment. Front. Med. 10 , 1146115 (2023). 10.3389/fmed.2023.1146115 PMC10174294 37181357

37. Morita S Targeting ABL-IRE1alpha signaling spares ER-stressed pancreatic beta cells to reverse autoimmune diabetes Cell Metab. 2017 25 883 897 e888 10.1016/j.cmet.2017.03.018 28380378 PMC5497784 Morita, S. et al. Targeting ABL-IRE1alpha signaling spares ER-stressed pancreatic beta cells to reverse autoimmune diabetes. Cell Metab. 25 , 883–897 e888 (2017). 28380378 10.1016/j.cmet.2017.03.018 PMC5497784

38. Sheng X IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling Nat. Commun. 2019 10 323 10.1038/s41467-018-08152-3 30679434 PMC6345973 Sheng, X. et al. IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat. Commun. 10 , 323 (2019). 30679434 10.1038/s41467-018-08152-3 PMC6345973

39. Samanta S The hydroxyquinoline analogue YUM70 Inhibits GRP78 to induce ER stress-mediated apoptosis in pancreatic cancer Cancer Res. 2021 81 1883 1895 10.1158/0008-5472.CAN-20-1540 33531374 PMC8137563 Samanta, S. et al. The hydroxyquinoline analogue YUM70 Inhibits GRP78 to induce ER stress-mediated apoptosis in pancreatic cancer. Cancer Res. 81 , 1883–1895 (2021). 33531374 10.1158/0008-5472.CAN-20-1540 PMC8137563

40. Liu X ER-targeting PDT converts tumors into in situ therapeutic tumor vaccines ACS Nano 2022 16 9240 9253 10.1021/acsnano.2c01669 35713245 Liu, X. et al. ER-targeting PDT converts tumors into in situ therapeutic tumor vaccines. ACS Nano 16 , 9240–9253 (2022). 35713245 10.1021/acsnano.2c01669

41. Benson TW Gut microbiota-derived trimethylamine N-Oxide contributes to abdominal aortic aneurysm through inflammatory and apoptotic mechanisms Circulation 2023 147 1079 1096 10.1161/CIRCULATIONAHA.122.060573 37011073 PMC10071415 Benson, T. W. et al. Gut microbiota-derived trimethylamine N-Oxide contributes to abdominal aortic aneurysm through inflammatory and apoptotic mechanisms. Circulation 147 , 1079–1096 (2023). 37011073 10.1161/CIRCULATIONAHA.122.060573 PMC10071415

42. Xu L IRE1alpha silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer Cell 2024 187 7248 7266.e7234 10.1016/j.cell.2024.09.032 39419025 PMC11645245 Xu, L. et al. IRE1alpha silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer. Cell 187 , 7248–7266.e7234 (2024). 39419025 10.1016/j.cell.2024.09.032 PMC11645245

43. Acosta-Alvear, D., Harnoss, J. M., Walter, P. & Ashkenazi, A. Homeostasis control in health and disease by the unfolded protein response. Nat. Rev. Mol. Cell Biol . 26 , 193-212 (2024). 10.1038/s41580-024-00794-0 39501044

44. Senft D Ronai ZA UPR, autophagy, and mitochondria crosstalk underlies the ER stress response Trends Biochem. Sci. 2015 40 141 148 10.1016/j.tibs.2015.01.002 25656104 PMC4340752 Senft, D. & Ronai, Z. A. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 40 , 141–148 (2015). 25656104 10.1016/j.tibs.2015.01.002 PMC4340752

45. Pincus D BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response PLoS Biol. 2010 8 e1000415 10.1371/journal.pbio.1000415 20625545 PMC2897766 Pincus, D. et al. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 8 , e1000415 (2010). 20625545 10.1371/journal.pbio.1000415 PMC2897766

46. Tirasophon W Welihinda AA Kaufman RJ A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells Genes Dev. 1998 12 1812 1824 10.1101/gad.12.12.1812 9637683 PMC316900 Tirasophon, W., Welihinda, A. A. & Kaufman, R. J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12 , 1812–1824 (1998). 9637683 10.1101/gad.12.12.1812 PMC316900

47. Credle JJ On the mechanism of sensing unfolded protein in the endoplasmic reticulum Proc. Natl. Acad. Sci. USA 2005 102 18773 18784 10.1073/pnas.0509487102 16365312 PMC1316886 Credle, J. J. et al. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 102 , 18773–18784 (2005). 16365312 10.1073/pnas.0509487102 PMC1316886

48. Liang, W. et al. Necroptosis activates UPR sensors without disrupting their binding with GRP78. Proc. Natl. Acad. Sci. USA . 118 , e2110476118 (2021). 10.1073/pnas.2110476118 PMC8488584 34544877

49. Sha H He Y Yang L Qi L Stressed out about obesity: IRE1alpha-XBP1 in metabolic disorders Trends Endocrinol. Metab. 2011 22 374 381 10.1016/j.tem.2011.05.002 21703863 PMC3163776 Sha, H., He, Y., Yang, L. & Qi, L. Stressed out about obesity: IRE1alpha-XBP1 in metabolic disorders. Trends Endocrinol. Metab. 22 , 374–381 (2011). 21703863 10.1016/j.tem.2011.05.002 PMC3163776

50. Cubillos-Ruiz JR Bettigole SE Glimcher LH Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer Cell 2017 168 692 706 10.1016/j.cell.2016.12.004 28187289 PMC5333759 Cubillos-Ruiz, J. R., Bettigole, S. E. & Glimcher, L. H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell 168 , 692–706 (2017). 28187289 10.1016/j.cell.2016.12.004 PMC5333759

51. Le Thomas A Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1alpha Nat. Commun. 2021 12 7310 10.1038/s41467-021-27597-7 34911951 PMC8674358 Le Thomas, A. et al. Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1alpha. Nat. Commun. 12 , 7310 (2021). 34911951 10.1038/s41467-021-27597-7 PMC8674358

52. Madhavan A Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity Nat. Commun. 2022 13 608 10.1038/s41467-022-28271-2 35105890 PMC8807832 Madhavan, A. et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nat. Commun. 13 , 608 (2022). 35105890 10.1038/s41467-022-28271-2 PMC8807832

53. Thuerauf DJ Marcinko M Belmont PJ Glembotski CC Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability J. Biol. Chem. 2007 282 22865 22878 10.1074/jbc.M701213200 17522056 Thuerauf, D. J., Marcinko, M., Belmont, P. J. & Glembotski, C. C. Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. J. Biol. Chem. 282 , 22865–22878 (2007). 17522056 10.1074/jbc.M701213200

54. Yamamoto K Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1 Dev. Cell 2007 13 365 376 10.1016/j.devcel.2007.07.018 17765680 Yamamoto, K. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev. Cell 13 , 365–376 (2007). 17765680 10.1016/j.devcel.2007.07.018

55. Cubillos-Ruiz, J. R., Mohamed, E. & Rodriguez, P. C. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J. Immunother. Cancer . 5 , 5 (2017). 10.1186/s40425-016-0203-4 PMC5240216 28105371

56. Shaffer AL XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation Immunity 2004 21 81 93 10.1016/j.immuni.2004.06.010 15345222 Shaffer, A. L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21 , 81–93 (2004). 15345222 10.1016/j.immuni.2004.06.010

57. Kopp MC UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor Nat. Struct. Mol. Biol. 2019 26 1053 1062 10.1038/s41594-019-0324-9 31695187 PMC6858872 Kopp, M. C. et al. UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nat. Struct. Mol. Biol. 26 , 1053–1062 (2019). 31695187 10.1038/s41594-019-0324-9 PMC6858872

58. Xu F COPII mitigates ER stress by promoting formation of ER whorls Cell Res. 2021 31 141 156 10.1038/s41422-020-00416-2 32989223 PMC8026990 Xu, F. et al. COPII mitigates ER stress by promoting formation of ER whorls. Cell Res. 31 , 141–156 (2021). 32989223 10.1038/s41422-020-00416-2 PMC8026990

59. Verfaillie T PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress Cell Death Differ. 2012 19 1880 1891 10.1038/cdd.2012.74 22705852 PMC3469056 Verfaillie, T. et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19 , 1880–1891 (2012). 22705852 10.1038/cdd.2012.74 PMC3469056

60. Smalinskaite L Mechanism of an intramembrane chaperone for multipass membrane proteins Nature 2022 611 161 166 10.1038/s41586-022-05336-2 36261528 PMC7614104 Smalinskaite, L. et al. Mechanism of an intramembrane chaperone for multipass membrane proteins. Nature 611 , 161–166 (2022). 36261528 10.1038/s41586-022-05336-2 PMC7614104

61. Bhatia S Udgaonkar JB Heterogeneity in protein folding and unfolding reactions Chem. Rev. 2022 122 8911 8935 10.1021/acs.chemrev.1c00704 35275612 Bhatia, S. & Udgaonkar, J. B. Heterogeneity in protein folding and unfolding reactions. Chem. Rev. 122 , 8911–8935 (2022). 35275612 10.1021/acs.chemrev.1c00704

62. Collins GA Goldberg AL The logic of the 26S proteasome Cell 2017 169 792 806 10.1016/j.cell.2017.04.023 28525752 PMC5609836 Collins, G. A. & Goldberg, A. L. The logic of the 26S proteasome. Cell 169 , 792–806 (2017). 28525752 10.1016/j.cell.2017.04.023 PMC5609836

63. Feng YX Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to endoplasmic reticulum stress Cancer Discov. 2014 4 702 715 10.1158/2159-8290.CD-13-0945 24705811 Feng, Y. X. et al. Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to endoplasmic reticulum stress. Cancer Discov. 4 , 702–715 (2014). 24705811 10.1158/2159-8290.CD-13-0945

64. Babour A Bicknell AA Tourtellotte J Niwa M A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance Cell 2010 142 256 269 10.1016/j.cell.2010.06.006 20619447 PMC3359143 Babour, A., Bicknell, A. A., Tourtellotte, J. & Niwa, M. A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance. Cell 142 , 256–269 (2010). 20619447 10.1016/j.cell.2010.06.006 PMC3359143

65. Rowland AA Voeltz GK Endoplasmic reticulum-mitochondria contacts: function of the junction Nat. Rev. Mol. Cell Biol. 2012 13 607 625 10.1038/nrm3440 22992592 PMC5111635 Rowland, A. A. & Voeltz, G. K. Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat. Rev. Mol. Cell Biol. 13 , 607–625 (2012). 22992592 10.1038/nrm3440 PMC5111635

66. Chernorudskiy A Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity Proc. Natl. Acad. Sci. USA 2020 117 21288 21298 10.1073/pnas.2003847117 32817544 PMC7474598 Chernorudskiy, A. et al. Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity. Proc. Natl. Acad. Sci. USA 117 , 21288–21298 (2020). 32817544 10.1073/pnas.2003847117 PMC7474598

67. Ureshino, R. P. et al. The interplay between Ca(2+) signaling pathways and neurodegeneration. Int. J. Mol. Sci . 20 , 6004 (2019). 10.3390/ijms20236004 PMC6928941 31795242

68. Dong Y Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo Circulation 2010 121 792 803 10.1161/CIRCULATIONAHA.109.900928 20124121 PMC2825900 Dong, Y. et al. Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121 , 792–803 (2010). 20124121 10.1161/CIRCULATIONAHA.109.900928 PMC2825900

69. Collins HE Novel role of the ER/SR Ca(2+) sensor STIM1 in the regulation of cardiac metabolism Am. J. Physiol. Heart Circ. Physiol. 2019 316 H1014 H1026 10.1152/ajpheart.00544.2018 30575437 PMC6580390 Collins, H. E. et al. Novel role of the ER/SR Ca(2+) sensor STIM1 in the regulation of cardiac metabolism. Am. J. Physiol. Heart Circ. Physiol. 316 , H1014–H1026 (2019). 30575437 10.1152/ajpheart.00544.2018 PMC6580390

70. Hamada K Mikoshiba K IP(3) receptor plasticity underlying diverse functions Annu. Rev. Physiol. 2020 82 151 176 10.1146/annurev-physiol-021119-034433 31730387 Hamada, K. & Mikoshiba, K. IP(3) receptor plasticity underlying diverse functions. Annu. Rev. Physiol. 82 , 151–176 (2020). 31730387 10.1146/annurev-physiol-021119-034433

71. Forrester, A. et al. A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex. EMBO J . 38 , e99847 (2019). 10.15252/embj.201899847 PMC6331724 30559329

72. Jutzi JS CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response Leukemia 2023 37 359 369 10.1038/s41375-022-01781-0 36473980 PMC12413246 Jutzi, J. S. et al. CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response. Leukemia 37 , 359–369 (2023). 36473980 10.1038/s41375-022-01781-0 PMC12413246

73. Fucikova J Spisek R Kroemer G Galluzzi L Calreticulin and cancer Cell Res 2021 31 5 16 10.1038/s41422-020-0383-9 32733014 PMC7853084 Fucikova, J., Spisek, R., Kroemer, G. & Galluzzi, L. Calreticulin and cancer. Cell Res 31 , 5–16 (2021). 32733014 10.1038/s41422-020-0383-9 PMC7853084

74. Varlamova, E. G. et al. Comparative analysis of the cytotoxic effect of a complex of selenium nanoparticles doped with sorafenib, “naked” selenium nanoparticles, and sorafenib on human hepatocyte carcinoma HepG2 cells. Int. J. Mol. Sci . 23 , 6641 (2022). 10.3390/ijms23126641 PMC9223423 35743086

75. Saiki S Sato S Hattori N Molecular pathogenesis of Parkinson’s disease: update J. Neurol. Neurosurg. Psychiatry 2012 83 430 436 10.1136/jnnp-2011-301205 22138181 Saiki, S., Sato, S. & Hattori, N. Molecular pathogenesis of Parkinson’s disease: update. J. Neurol. Neurosurg. Psychiatry 83 , 430–436 (2012). 22138181 10.1136/jnnp-2011-301205

76. Lee J Di Jeso B Arvan P The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone J. Clin. Invest. 2008 118 2950 2958 10.1172/JCI35164 18596923 PMC2441857 Lee, J., Di Jeso, B. & Arvan, P. The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone. J. Clin. Invest. 118 , 2950–2958 (2008). 18596923 10.1172/JCI35164 PMC2441857

77. Liu Q HOMER3 facilitates growth factor-mediated beta-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer J. Hematol. Oncol. 2021 14 6 10.1186/s13045-020-01021-x 33407765 PMC7788750 Liu, Q. et al. HOMER3 facilitates growth factor-mediated beta-Catenin tyrosine phosphorylation and activation to promote metastasis in triple negative breast cancer. J. Hematol. Oncol. 14 , 6 (2021). 33407765 10.1186/s13045-020-01021-x PMC7788750

78. Chen X Cubillos-Ruiz JR Endoplasmic reticulum stress signals in the tumour and its microenvironment Nat. Rev. Cancer 2021 21 71 88 10.1038/s41568-020-00312-2 33214692 PMC7927882 Chen, X. & Cubillos-Ruiz, J. R. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer 21 , 71–88 (2021). 33214692 10.1038/s41568-020-00312-2 PMC7927882

79. Signer RA Magee JA Salic A Morrison SJ Haematopoietic stem cells require a highly regulated protein synthesis rate Nature 2014 509 49 54 10.1038/nature13035 24670665 PMC4015626 Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509 , 49–54 (2014). 24670665 10.1038/nature13035 PMC4015626

80. Ozcan U Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis Mol. Cell 2008 29 541 551 10.1016/j.molcel.2007.12.023 18342602 PMC2361721 Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29 , 541–551 (2008). 18342602 10.1016/j.molcel.2007.12.023 PMC2361721

81. Corazzari M Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma Cell Death Differ. 2015 22 946 958 10.1038/cdd.2014.183 25361077 PMC4423179 Corazzari, M. et al. Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma. Cell Death Differ. 22 , 946–958 (2015). 25361077 10.1038/cdd.2014.183 PMC4423179

82. Graff J Kim D Dobbin MM Tsai LH Epigenetic regulation of gene expression in physiological and pathological brain processes Physiol. Rev. 2011 91 603 649 10.1152/physrev.00012.2010 21527733 Graff, J., Kim, D., Dobbin, M. M. & Tsai, L. H. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol. Rev. 91 , 603–649 (2011). 21527733 10.1152/physrev.00012.2010

83. Chen X Endoplasmic reticulum stress: molecular mechanism and therapeutic targets Signal Transduct. Target. Ther. 2023 8 352 10.1038/s41392-023-01570-w 37709773 PMC10502142 Chen, X. et al. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct. Target. Ther. 8 , 352 (2023). 37709773 10.1038/s41392-023-01570-w PMC10502142

84. Sabari BR Zhang D Allis CD Zhao Y Metabolic regulation of gene expression through histone acylations Nat. Rev. Mol. Cell Biol. 2017 18 90 101 10.1038/nrm.2016.140 27924077 PMC5320945 Sabari, B. R., Zhang, D., Allis, C. D. & Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 18 , 90–101 (2017). 27924077 10.1038/nrm.2016.140 PMC5320945

85. Diaz-Bulnes, P. et al. Demethylation of H3K9 and H3K27 contributes to the tubular renal damage triggered by endoplasmic reticulum stress. Antioxidants 11 , 1355 (2022). 10.3390/antiox11071355 PMC9312208 35883846

86. Li J Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets J. Hepatol. 2012 56 900 907 10.1016/j.jhep.2011.10.018 22173165 Li, J. et al. Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets. J. Hepatol. 56 , 900–907 (2012). 22173165 10.1016/j.jhep.2011.10.018

87. Boyman L Karbowski M Lederer WJ Regulation of mitochondrial ATP production: Ca(2+) signaling and quality control Trends Mol. Med. 2020 26 21 39 10.1016/j.molmed.2019.10.007 31767352 PMC7921598 Boyman, L., Karbowski, M. & Lederer, W. J. Regulation of mitochondrial ATP production: Ca(2+) signaling and quality control. Trends Mol. Med. 26 , 21–39 (2020). 31767352 10.1016/j.molmed.2019.10.007 PMC7921598

88. Csordas G Weaver D Hajnoczky G Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions Trends Cell Biol. 2018 28 523 540 10.1016/j.tcb.2018.02.009 29588129 PMC6005738 Csordas, G., Weaver, D. & Hajnoczky, G. Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions. Trends Cell Biol. 28 , 523–540 (2018). 29588129 10.1016/j.tcb.2018.02.009 PMC6005738

89. Costa R Impaired mitochondrial ATP production downregulates Wnt signaling via ER stress induction Cell Rep. 2019 28 1949 1960 e1946 10.1016/j.celrep.2019.07.050 31433973 Costa, R. et al. Impaired mitochondrial ATP production downregulates Wnt signaling via ER stress induction. Cell Rep. 28 , 1949–1960 e1946 (2019). 31433973 10.1016/j.celrep.2019.07.050

90. Zhu X Wang K Zhou F Zhu L Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca(2+)/CaMKII-dependent activation of AMPK Arch. Pharm. Res. 2018 41 1009 1018 10.1007/s12272-018-1059-6 30117083 Zhu, X., Wang, K., Zhou, F. & Zhu, L. Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca(2+)/CaMKII-dependent activation of AMPK. Arch. Pharm. Res. 41 , 1009–1018 (2018). 30117083 10.1007/s12272-018-1059-6

91. Loncke J Balancing ER-mitochondrial Ca(2+) fluxes in health and disease Trends Cell Biol. 2021 31 598 612 10.1016/j.tcb.2021.02.003 33678551 PMC8195822 Loncke, J. et al. Balancing ER-mitochondrial Ca(2+) fluxes in health and disease. Trends Cell Biol. 31 , 598–612 (2021). 33678551 10.1016/j.tcb.2021.02.003 PMC8195822

92. Biczo G Mitochondrial dysfunction, through impaired autophagy, leads to endoplasmic reticulum stress, deregulated lipid metabolism, and pancreatitis in animal models Gastroenterology 2018 154 689 703 10.1053/j.gastro.2017.10.012 29074451 PMC6369139 Biczo, G. et al. Mitochondrial dysfunction, through impaired autophagy, leads to endoplasmic reticulum stress, deregulated lipid metabolism, and pancreatitis in animal models. Gastroenterology 154 , 689–703 (2018). 29074451 10.1053/j.gastro.2017.10.012 PMC6369139

93. Nakagawa T Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta Nature 2000 403 98 103 10.1038/47513 10638761 Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403 , 98–103 (2000). 10638761 10.1038/47513

94. Icard P How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist. Updat. 2018 38 1 11 10.1016/j.drup.2018.03.001 29857814 Icard, P. et al. How the Warburg effect supports aggressiveness and drug resistance of cancer cells?. Drug Resist. Updat. 38 , 1–11 (2018). 29857814 10.1016/j.drup.2018.03.001

95. Kaelin WG Jr Ratcliffe PJ Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway Mol. Cell 2008 30 393 402 10.1016/j.molcel.2008.04.009 18498744 Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30 , 393–402 (2008). 18498744 10.1016/j.molcel.2008.04.009

96. Mennerich D ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/betaTrCP Redox Biol. 2022 50 102243 10.1016/j.redox.2022.102243 35074541 PMC8792260 Mennerich, D. et al. ER-stress promotes VHL-independent degradation of hypoxia-inducible factors via FBXW1A/betaTrCP. Redox Biol. 50 , 102243 (2022). 35074541 10.1016/j.redox.2022.102243 PMC8792260

97. Bechmann LP The interaction of hepatic lipid and glucose metabolism in liver diseases J. Hepatol. 2012 56 952 964 10.1016/j.jhep.2011.08.025 22173168 Bechmann, L. P. et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. 56 , 952–964 (2012). 22173168 10.1016/j.jhep.2011.08.025

98. Feng Y Interplay of energy metabolism and autophagy Autophagy 2024 20 4 14 10.1080/15548627.2023.2247300 37594406 PMC10761056 Feng, Y. et al. Interplay of energy metabolism and autophagy. Autophagy 20 , 4–14 (2024). 37594406 10.1080/15548627.2023.2247300 PMC10761056

99. Yang X IDH1, a CHOP and C/EBPbeta-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis Cancer Lett. 2015 365 201 210 10.1016/j.canlet.2015.05.027 26049021 Yang, X. et al. IDH1, a CHOP and C/EBPbeta-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis. Cancer Lett. 365 , 201–210 (2015). 26049021 10.1016/j.canlet.2015.05.027

100. Huber AL p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose Mol. Cell 2013 49 1049 1059 10.1016/j.molcel.2013.01.009 23395000 Huber, A. L. et al. p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Mol. Cell 49 , 1049–1059 (2013). 23395000 10.1016/j.molcel.2013.01.009

101. Chaudhary, V. et al. Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses. J. Exp. Med . 219 , e20221085 (2022). 10.1084/jem.20221085 PMC9441715 36053251

102. Samuel VT Shulman GI Mechanisms for insulin resistance: common threads and missing links Cell 2012 148 852 871 10.1016/j.cell.2012.02.017 22385956 PMC3294420 Samuel, V. T. & Shulman, G. I. Mechanisms for insulin resistance: common threads and missing links. Cell 148 , 852–871 (2012). 22385956 10.1016/j.cell.2012.02.017 PMC3294420

103. Sutton-McDowall ML Nonesterified fatty acid-induced endoplasmic reticulum stress in cattle cumulus oocyte complexes alters cell metabolism and developmental competence Biol. Reprod. 2016 94 23 10.1095/biolreprod.115.131862 26658709 Sutton-McDowall, M. L. et al. Nonesterified fatty acid-induced endoplasmic reticulum stress in cattle cumulus oocyte complexes alters cell metabolism and developmental competence. Biol. Reprod. 94 , 23 (2016). 26658709 10.1095/biolreprod.115.131862

104. Sun X Deletion of the pH sensor GPR4 decreases renal acid excretion J. Am. Soc. Nephrol. 2010 21 1745 1755 10.1681/ASN.2009050477 20798260 PMC3013533 Sun, X. et al. Deletion of the pH sensor GPR4 decreases renal acid excretion. J. Am. Soc. Nephrol. 21 , 1745–1755 (2010). 20798260 10.1681/ASN.2009050477 PMC3013533

105. Wang Y Patti GJ The Warburg effect: a signature of mitochondrial overload Trends Cell Biol. 2023 33 1014 1020 10.1016/j.tcb.2023.03.013 37117116 PMC10600323 Wang, Y. & Patti, G. J. The Warburg effect: a signature of mitochondrial overload. Trends Cell Biol. 33 , 1014–1020 (2023). 37117116 10.1016/j.tcb.2023.03.013 PMC10600323

106. Tang X Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs Cancer Res. 2012 72 491 502 10.1158/0008-5472.CAN-11-2076 22135092 PMC3261313 Tang, X. et al. Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs. Cancer Res. 72 , 491–502 (2012). 22135092 10.1158/0008-5472.CAN-11-2076 PMC3261313

107. Sun Z Lactate activates ER stress to promote alveolar epithelial cells apoptosis in pulmonary fibrosis Respir. Res. 2024 25 401 10.1186/s12931-024-03016-5 39522031 PMC11550544 Sun, Z. et al. Lactate activates ER stress to promote alveolar epithelial cells apoptosis in pulmonary fibrosis. Respir. Res. 25 , 401 (2024). 39522031 10.1186/s12931-024-03016-5 PMC11550544

108. Sharma V Kaur R Bhatnagar A Kaur J Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling Cell Stress Chaperones 2015 20 431 440 10.1007/s12192-014-0568-6 25823563 PMC4406939 Sharma, V., Kaur, R., Bhatnagar, A. & Kaur, J. Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling. Cell Stress Chaperones 20 , 431–440 (2015). 25823563 10.1007/s12192-014-0568-6 PMC4406939

109. Dong, L., Krewson, E. A. & Yang, L. V. Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. Int. J. Mol. Sci . 18 , 278 (2017). 10.3390/ijms18020278 PMC5343814 28134810

110. Ali MM Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response EMBO J. 2011 30 894 905 10.1038/emboj.2011.18 21317875 PMC3049214 Ali, M. M. et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. EMBO J. 30 , 894–905 (2011). 21317875 10.1038/emboj.2011.18 PMC3049214

111. Hui B Exosomes secreted by Fusobacterium nucleatum-infected colon cancer cells transmit resistance to oxaliplatin and 5-FU by delivering hsa_circ_0004085 J. Nanobiotechnology 2024 22 62 10.1186/s12951-024-02331-9 38360615 PMC10867993 Hui, B. et al. Exosomes secreted by Fusobacterium nucleatum-infected colon cancer cells transmit resistance to oxaliplatin and 5-FU by delivering hsa_circ_0004085. J. Nanobiotechnology 22 , 62 (2024). 38360615 10.1186/s12951-024-02331-9 PMC10867993

112. Abhishek, K. et al. Phosphorylation of translation initiation factor 2-alpha in Leishmania donovani under stress is necessary for parasite survival. Mol. Cell Biol . 37 , e00344-16 (2017). 10.1128/MCB.00344-16 PMC5192082 27736773

113. Forman HJ Zhang H Targeting oxidative stress in disease: promise and limitations of antioxidant therapy Nat. Rev. Drug Discov. 2021 20 689 709 10.1038/s41573-021-00233-1 34194012 PMC8243062 Forman, H. J. & Zhang, H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat. Rev. Drug Discov. 20 , 689–709 (2021). 34194012 10.1038/s41573-021-00233-1 PMC8243062

114. van der Pol A van Gilst WH Voors AA van der Meer P Treating oxidative stress in heart failure: past, present and future Eur. J. Heart Fail. 2019 21 425 435 10.1002/ejhf.1320 30338885 PMC6607515 van der Pol, A., van Gilst, W. H., Voors, A. A. & van der Meer, P. Treating oxidative stress in heart failure: past, present and future. Eur. J. Heart Fail. 21 , 425–435 (2019). 30338885 10.1002/ejhf.1320 PMC6607515

115. Ornatowski W Complex interplay between autophagy and oxidative stress in the development of pulmonary disease Redox Biol. 2020 36 101679 10.1016/j.redox.2020.101679 32818797 PMC7451718 Ornatowski, W. et al. Complex interplay between autophagy and oxidative stress in the development of pulmonary disease. Redox Biol. 36 , 101679 (2020). 32818797 10.1016/j.redox.2020.101679 PMC7451718

116. Liu Y TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway Nat. Commun. 2020 11 348 10.1038/s41467-019-14190-2 31953436 PMC6969153 Liu, Y. et al. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat. Commun. 11 , 348 (2020). 31953436 10.1038/s41467-019-14190-2 PMC6969153

117. Yang YM Chaperone-directed ribosome repair after oxidative damage Mol. Cell 2023 83 1527 1537.e1525 10.1016/j.molcel.2023.03.030 37086725 PMC10164075 Yang, Y. M. et al. Chaperone-directed ribosome repair after oxidative damage. Mol. Cell 83 , 1527–1537.e1525 (2023). 37086725 10.1016/j.molcel.2023.03.030 PMC10164075

118. Jin JK ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart Circ. Res. 2017 120 862 875 10.1161/CIRCRESAHA.116.310266 27932512 PMC5336510 Jin, J. K. et al. ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart. Circ. Res. 120 , 862–875 (2017). 27932512 10.1161/CIRCRESAHA.116.310266 PMC5336510

119. Kim EJ Lee YJ Kang S Lim YB Ionizing radiation activates PERK/eIF2alpha/ATF4 signaling via ER stress-independent pathway in human vascular endothelial cells Int. J. Radiat. Biol. 2014 90 306 312 10.3109/09553002.2014.886793 24456547 Kim, E. J., Lee, Y. J., Kang, S. & Lim, Y. B. Ionizing radiation activates PERK/eIF2alpha/ATF4 signaling via ER stress-independent pathway in human vascular endothelial cells. Int. J. Radiat. Biol. 90 , 306–312 (2014). 24456547 10.3109/09553002.2014.886793

120. Kepp O Crosstalk between ER stress and immunogenic cell death Cytokine Growth Factor Rev. 2013 24 311 318 10.1016/j.cytogfr.2013.05.001 23787159 Kepp, O. et al. Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev. 24 , 311–318 (2013). 23787159 10.1016/j.cytogfr.2013.05.001

121. Pozzi C The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death Nat. Med. 2016 22 624 631 10.1038/nm.4078 27135741 Pozzi, C. et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 22 , 624–631 (2016). 27135741 10.1038/nm.4078

122. Jeon YJ Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies Cancer Cell 2015 27 354 369 10.1016/j.ccell.2015.02.006 25759021 PMC4356903 Jeon, Y. J. et al. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 27 , 354–369 (2015). 25759021 10.1016/j.ccell.2015.02.006 PMC4356903

123. Broekgaarden M Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies Cancer Metastasis Rev. 2015 34 643 690 10.1007/s10555-015-9588-7 26516076 PMC4661210 Broekgaarden, M. et al. Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev. 34 , 643–690 (2015). 26516076 10.1007/s10555-015-9588-7 PMC4661210

124. Hwang J Qi L Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways Trends Biochem. Sci. 2018 43 593 605 10.1016/j.tibs.2018.06.005 30056836 PMC6327314 Hwang, J. & Qi, L. Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways. Trends Biochem. Sci. 43 , 593–605 (2018). 30056836 10.1016/j.tibs.2018.06.005 PMC6327314

125. Krshnan, L., van de Weijer, M. L. & Carvalho, P. Endoplasmic reticulum-associated protein degradation. Cold Spring Harb. Perspect. Biol . 14 , a041247 (2022). 10.1101/cshperspect.a041247 PMC9732900 35940909

126. Urano F Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 Science 2000 287 664 666 10.1126/science.287.5453.664 10650002 Urano, F. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287 , 664–666 (2000). 10650002 10.1126/science.287.5453.664

127. Shinkai Y Yamamoto C Kaji T Lead induces the expression of endoplasmic reticulum chaperones GRP78 and GRP94 in vascular endothelial cells via the JNK-AP-1 pathway Toxicol. Sci. 2010 114 378 386 10.1093/toxsci/kfq008 20071421 Shinkai, Y., Yamamoto, C. & Kaji, T. Lead induces the expression of endoplasmic reticulum chaperones GRP78 and GRP94 in vascular endothelial cells via the JNK-AP-1 pathway. Toxicol. Sci. 114 , 378–386 (2010). 20071421 10.1093/toxsci/kfq008

128. Li GJ MiR-137 regulates low-intensity shear stress-induced human aortic endothelial cell apoptosis via JNK/AP-1 signaling J. Physiol. Biochem. 2021 77 451 460 10.1007/s13105-021-00812-1 33893994 Li, G. J. et al. MiR-137 regulates low-intensity shear stress-induced human aortic endothelial cell apoptosis via JNK/AP-1 signaling. J. Physiol. Biochem. 77 , 451–460 (2021). 33893994 10.1007/s13105-021-00812-1

129. Liang Y Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production J. Cell Mol. Med. 2020 24 13408 13420 10.1111/jcmm.15964 33043579 PMC7701502 Liang, Y. et al. Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production. J. Cell Mol. Med. 24 , 13408–13420 (2020). 33043579 10.1111/jcmm.15964 PMC7701502

130. Pelizzari-Raymundo D IRE1 RNase controls CD95-mediated cell death EMBO Rep. 2024 25 1792 1813 10.1038/s44319-024-00095-9 38383861 PMC11014915 Pelizzari-Raymundo, D. et al. IRE1 RNase controls CD95-mediated cell death. EMBO Rep. 25 , 1792–1813 (2024). 38383861 10.1038/s44319-024-00095-9 PMC11014915

131. DenBoer LM Luman is capable of binding and activating transcription from the unfolded protein response element Biochem. Biophys. Res. Commun. 2005 331 113 119 10.1016/j.bbrc.2005.03.141 15845366 DenBoer, L. M. et al. Luman is capable of binding and activating transcription from the unfolded protein response element. Biochem. Biophys. Res. Commun. 331 , 113–119 (2005). 15845366 10.1016/j.bbrc.2005.03.141

132. Yoshida H A time-dependent phase shift in the mammalian unfolded protein response Dev. Cell 2003 4 265 271 10.1016/S1534-5807(03)00022-4 12586069 Yoshida, H. et al. A time-dependent phase shift in the mammalian unfolded protein response. Dev. Cell 4 , 265–271 (2003). 12586069 10.1016/s1534-5807(03)00022-4

133. Gan L Ischemic heart-derived small extracellular vesicles impair adipocyte function Circ. Res. 2022 130 48 66 10.1161/CIRCRESAHA.121.320157 34763521 Gan, L. et al. Ischemic heart-derived small extracellular vesicles impair adipocyte function. Circ. Res. 130 , 48–66 (2022). 34763521 10.1161/CIRCRESAHA.121.320157

134. Kaneko M Nomura Y ER signaling in unfolded protein response Life Sci. 2003 74 199 205 10.1016/j.lfs.2003.09.007 14607247 Kaneko, M. & Nomura, Y. ER signaling in unfolded protein response. Life Sci. 74 , 199–205 (2003). 14607247 10.1016/j.lfs.2003.09.007

135. Carvajal P hsa-miR-424-5p and hsa-miR-513c-3p dysregulation mediated by IFN-gamma is associated with salivary gland dysfunction in Sjogren’s syndrome patients J. Autoimmun. 2023 138 103037 10.1016/j.jaut.2023.103037 37229808 Carvajal, P. et al. hsa-miR-424-5p and hsa-miR-513c-3p dysregulation mediated by IFN-gamma is associated with salivary gland dysfunction in Sjogren’s syndrome patients. J. Autoimmun. 138 , 103037 (2023). 37229808 10.1016/j.jaut.2023.103037

136. Barrera MJ Pro-inflammatory cytokines enhance ERAD and ATF6alpha pathway activity in salivary glands of Sjogren’s syndrome patients J. Autoimmun. 2016 75 68 81 10.1016/j.jaut.2016.07.006 27461470 Barrera, M. J. et al. Pro-inflammatory cytokines enhance ERAD and ATF6alpha pathway activity in salivary glands of Sjogren’s syndrome patients. J. Autoimmun. 75 , 68–81 (2016). 27461470 10.1016/j.jaut.2016.07.006

137. Xue M Irshad Z Rabbani N Thornalley PJ Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response Redox Biol. 2024 69 103025 10.1016/j.redox.2024.103025 38199038 PMC10821617 Xue, M., Irshad, Z., Rabbani, N. & Thornalley, P. J. Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response. Redox Biol. 69 , 103025 (2024). 38199038 10.1016/j.redox.2024.103025 PMC10821617

138. Hung CT Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFbeta signalling Gut 2022 71 1876 1891 10.1136/gutjnl-2021-325065 34933915 Hung, C. T. et al. Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFbeta signalling. Gut 71 , 1876–1891 (2022). 34933915 10.1136/gutjnl-2021-325065

139. Gade P An IFN-gamma-stimulated ATF6-C/EBP-beta-signaling pathway critical for the expression of death associated protein kinase 1 and induction of autophagy Proc. Natl. Acad. Sci. USA 2012 109 10316 10321 10.1073/pnas.1119273109 22699507 PMC3387052 Gade, P. et al. An IFN-gamma-stimulated ATF6-C/EBP-beta-signaling pathway critical for the expression of death associated protein kinase 1 and induction of autophagy. Proc. Natl. Acad. Sci. USA 109 , 10316–10321 (2012). 22699507 10.1073/pnas.1119273109 PMC3387052

140. Tsutsumi S Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells Oncogene 2006 25 1018 1029 10.1038/sj.onc.1209139 16205636 Tsutsumi, S. et al. Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells. Oncogene 25 , 1018–1029 (2006). 16205636 10.1038/sj.onc.1209139

141. Novoa I Zeng H Harding HP Ron D Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha J. Cell Biol. 2001 153 1011 1022 10.1083/jcb.153.5.1011 11381086 PMC2174339 Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153 , 1011–1022 (2001). 11381086 10.1083/jcb.153.5.1011 PMC2174339

142. Sciarretta S Volpe M Sadoshima J NOX4 regulates autophagy during energy deprivation Autophagy 2014 10 699 701 10.4161/auto.27955 24492492 PMC4091158 Sciarretta, S., Volpe, M. & Sadoshima, J. NOX4 regulates autophagy during energy deprivation. Autophagy 10 , 699–701 (2014). 24492492 10.4161/auto.27955 PMC4091158

143. Jang JE PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells J. Exp. Clin. Cancer Res. 2020 39 66 10.1186/s13046-020-01565-3 32293500 PMC7158163 Jang, J. E. et al. PERK/NRF2 and autophagy form a resistance mechanism against G9a inhibition in leukemia stem cells. J. Exp. Clin. Cancer Res. 39 , 66 (2020). 32293500 10.1186/s13046-020-01565-3 PMC7158163

144. Mohamed E The unfolded protein response mediator PERK Governs myeloid cell-driven immunosuppression in tumors through inhibition of STING signaling Immunity 2020 52 668 682 e667 10.1016/j.immuni.2020.03.004 32294407 PMC7207019 Mohamed, E. et al. The unfolded protein response mediator PERK Governs myeloid cell-driven immunosuppression in tumors through inhibition of STING signaling. Immunity 52 , 668–682 e667 (2020). 32294407 10.1016/j.immuni.2020.03.004 PMC7207019

145. Liu, M. et al. PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen. J. Exp. Med . 219 , e20211498 (2022). 10.1084/jem.20211498 PMC8919616 35266960

146. Li C Caspase-3/GSDME dependent pyroptosis contributes to offspring lung injury induced by gestational PFOS exposure via PERK/ATF4 signaling Arch. Toxicol. 2024 98 207 221 10.1007/s00204-023-03626-w 37955688 PMC10761489 Li, C. et al. Caspase-3/GSDME dependent pyroptosis contributes to offspring lung injury induced by gestational PFOS exposure via PERK/ATF4 signaling. Arch. Toxicol. 98 , 207–221 (2024). 37955688 10.1007/s00204-023-03626-w PMC10761489

147. Wan H WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death Autophagy 2020 16 531 547 10.1080/15548627.2019.1630224 31204559 PMC6999610 Wan, H. et al. WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death. Autophagy 16 , 531–547 (2020). 31204559 10.1080/15548627.2019.1630224 PMC6999610

148. Di Conza G Ho PC Cubillos-Ruiz JR Huang SC Control of immune cell function by the unfolded protein response Nat. Rev. Immunol. 2023 23 546 562 10.1038/s41577-023-00838-0 36755160 Di Conza, G., Ho, P. C., Cubillos-Ruiz, J. R. & Huang, S. C. Control of immune cell function by the unfolded protein response. Nat. Rev. Immunol. 23 , 546–562 (2023). 36755160 10.1038/s41577-023-00838-0

149. Ji H Huang C Wu S Kasim V XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity Biochem. Biophys. Res. Commun. 2019 508 203 209 10.1016/j.bbrc.2018.11.112 30473215 Ji, H., Huang, C., Wu, S. & Kasim, V. XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity. Biochem. Biophys. Res. Commun. 508 , 203–209 (2019). 30473215 10.1016/j.bbrc.2018.11.112

150. Du Y Perfluorooctanoic acid exposure increases both proliferation and apoptosis of human placental trophoblast cells mediated by ER stress-induced ROS or UPR pathways Ecotoxicol. Environ. Saf. 2022 236 113508 10.1016/j.ecoenv.2022.113508 35427876 Du, Y. et al. Perfluorooctanoic acid exposure increases both proliferation and apoptosis of human placental trophoblast cells mediated by ER stress-induced ROS or UPR pathways. Ecotoxicol. Environ. Saf. 236 , 113508 (2022). 35427876 10.1016/j.ecoenv.2022.113508

151. Blazanin N ER stress and distinct outputs of the IRE1alpha RNase control proliferation and senescence in response to oncogenic Ras Proc. Natl. Acad. Sci. USA 2017 114 9900 9905 10.1073/pnas.1701757114 28847931 PMC5603998 Blazanin, N. et al. ER stress and distinct outputs of the IRE1alpha RNase control proliferation and senescence in response to oncogenic Ras. Proc. Natl. Acad. Sci. USA 114 , 9900–9905 (2017). 28847931 10.1073/pnas.1701757114 PMC5603998

152. Zhou AX C/EBP-homologous protein (CHOP) in vascular smooth muscle cells regulates their proliferation in aortic explants and atherosclerotic lesions Circ. Res. 2015 116 1736 1743 10.1161/CIRCRESAHA.116.305602 25872946 PMC4441876 Zhou, A. X. et al. C/EBP-homologous protein (CHOP) in vascular smooth muscle cells regulates their proliferation in aortic explants and atherosclerotic lesions. Circ. Res. 116 , 1736–1743 (2015). 25872946 10.1161/CIRCRESAHA.116.305602 PMC4441876

153. Auf G Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma Proc. Natl. Acad. Sci. USA 2010 107 15553 15558 10.1073/pnas.0914072107 20702765 PMC2932600 Auf, G. et al. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc. Natl. Acad. Sci. USA 107 , 15553–15558 (2010). 20702765 10.1073/pnas.0914072107 PMC2932600

154. Mawambo G HIF1alpha-dependent hypoxia response in myeloid cells requires IRE1alpha J. Neuroinflammation 2023 20 145 10.1186/s12974-023-02793-y 37344842 PMC10286485 Mawambo, G. et al. HIF1alpha-dependent hypoxia response in myeloid cells requires IRE1alpha. J. Neuroinflammation 20 , 145 (2023). 37344842 10.1186/s12974-023-02793-y PMC10286485

155. Tsai HL miR-148a inhibits early relapsed colorectal cancers and the secretion of VEGF by indirectly targeting HIF-1alpha under non-hypoxia/hypoxia conditions J. Cell Mol. Med. 2019 23 3572 3582 10.1111/jcmm.14257 30834693 PMC6484316 Tsai, H. L. et al. miR-148a inhibits early relapsed colorectal cancers and the secretion of VEGF by indirectly targeting HIF-1alpha under non-hypoxia/hypoxia conditions. J. Cell Mol. Med. 23 , 3572–3582 (2019). 30834693 10.1111/jcmm.14257 PMC6484316

156. Wang Y The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway Cancer Res. 2012 72 5396 5406 10.1158/0008-5472.CAN-12-0474 22915762 PMC3743425 Wang, Y. et al. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res. 72 , 5396–5406 (2012). 22915762 10.1158/0008-5472.CAN-12-0474 PMC3743425

157. Karali E VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress Mol. Cell 2014 54 559 572 10.1016/j.molcel.2014.03.022 24746698 Karali, E. et al. VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress. Mol. Cell 54 , 559–572 (2014). 24746698 10.1016/j.molcel.2014.03.022

158. Mujcic H Hypoxic activation of the PERK/eIF2alpha arm of the unfolded protein response promotes metastasis through induction of LAMP3 Clin. Cancer Res. 2013 19 6126 6137 10.1158/1078-0432.CCR-13-0526 24045183 Mujcic, H. et al. Hypoxic activation of the PERK/eIF2alpha arm of the unfolded protein response promotes metastasis through induction of LAMP3. Clin. Cancer Res. 19 , 6126–6137 (2013). 24045183 10.1158/1078-0432.CCR-13-0526

159. Wang SY COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer Cancer Lett. 2023 553 215995 10.1016/j.canlet.2022.215995 36336148 Wang, S. Y. et al. COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer. Cancer Lett. 553 , 215995 (2023). 36336148 10.1016/j.canlet.2022.215995

160. Yarapureddy S ATF6alpha activation enhances survival against chemotherapy and serves as a prognostic indicator in osteosarcoma Neoplasia 2019 21 516 532 10.1016/j.neo.2019.02.004 31029032 PMC6484364 Yarapureddy, S. et al. ATF6alpha activation enhances survival against chemotherapy and serves as a prognostic indicator in osteosarcoma. Neoplasia 21 , 516–532 (2019). 31029032 10.1016/j.neo.2019.02.004 PMC6484364

161. Jeon YJ miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC Nat. Commun. 2018 9 5110 10.1038/s41467-018-07561-8 30504895 PMC6269493 Jeon, Y. J. et al. miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC. Nat. Commun. 9 , 5110 (2018). 30504895 10.1038/s41467-018-07561-8 PMC6269493

162. Yoneda A Minomi K Tamura Y HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1alpha Oncogene 2020 39 4519 4537 10.1038/s41388-020-1311-7 32366908 Yoneda, A., Minomi, K. & Tamura, Y. HSP47 promotes metastasis of breast cancer by interacting with myosin IIA via the unfolded protein response transducer IRE1alpha. Oncogene 39 , 4519–4537 (2020). 32366908 10.1038/s41388-020-1311-7

163. Paez D Cancer dormancy: a model of early dissemination and late cancer recurrence Clin. Cancer Res. 2012 18 645 653 10.1158/1078-0432.CCR-11-2186 22156560 Paez, D. et al. Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin. Cancer Res. 18 , 645–653 (2012). 22156560 10.1158/1078-0432.CCR-11-2186

164. Calvo V A PERK-specific inhibitor blocks metastatic progression by limiting integrated stress response-dependent survival of quiescent cancer cells Clin. Cancer Res. 2023 29 5155 5172 10.1158/1078-0432.CCR-23-1427 37982738 PMC10842363 Calvo, V. et al. A PERK-specific inhibitor blocks metastatic progression by limiting integrated stress response-dependent survival of quiescent cancer cells. Clin. Cancer Res. 29 , 5155–5172 (2023). 37982738 10.1158/1078-0432.CCR-23-1427 PMC10842363

165. Senft D Ronai ZE Adaptive stress responses during tumor metastasis and Dormancy Trends Cancer 2016 2 429 442 10.1016/j.trecan.2016.06.004 27868104 PMC5114008 Senft, D. & Ronai, Z. E. Adaptive stress responses during tumor metastasis and Dormancy. Trends Cancer 2 , 429–442 (2016). 27868104 10.1016/j.trecan.2016.06.004 PMC5114008

166. Groenendyk J Biology of endoplasmic reticulum stress in the heart Circ. Res. 2010 107 1185 1197 10.1161/CIRCRESAHA.110.227033 21071716 Groenendyk, J. et al. Biology of endoplasmic reticulum stress in the heart. Circ. Res. 107 , 1185–1197 (2010). 21071716 10.1161/CIRCRESAHA.110.227033

167. Luciani DS Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death Diabetes 2009 58 422 432 10.2337/db07-1762 19033399 PMC2628616 Luciani, D. S. et al. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes 58 , 422–432 (2009). 19033399 10.2337/db07-1762 PMC2628616

168. Wu Y Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL Proc. Natl. Acad. Sci. USA 2018 115 E2762 E2771 10.1073/pnas.1716439115 29507230 PMC5866564 Wu, Y. et al. Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL. Proc. Natl. Acad. Sci. USA 115 , E2762–E2771 (2018). 29507230 10.1073/pnas.1716439115 PMC5866564

169. Bernales S McDonald KL Walter P Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response PLoS Biol. 2006 4 e423 10.1371/journal.pbio.0040423 17132049 PMC1661684 Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4 , e423 (2006). 17132049 10.1371/journal.pbio.0040423 PMC1661684

170. Matteoni S Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response J. Exp. Clin. Cancer Res. 2021 40 347 10.1186/s13046-021-02144-w 34740374 PMC8569984 Matteoni, S. et al. Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response. J. Exp. Clin. Cancer Res. 40 , 347 (2021). 34740374 10.1186/s13046-021-02144-w PMC8569984

171. Zhang Y Lentinan inhibited colon cancer growth by inducing endoplasmic reticulum stress-mediated autophagic cell death and apoptosis Carbohydr. Polym. 2021 267 118154 10.1016/j.carbpol.2021.118154 34119128 Zhang, Y. et al. Lentinan inhibited colon cancer growth by inducing endoplasmic reticulum stress-mediated autophagic cell death and apoptosis. Carbohydr. Polym. 267 , 118154 (2021). 34119128 10.1016/j.carbpol.2021.118154

172. Herrema H FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity Cell Metab. 2022 34 1004 1022.e1008 10.1016/j.cmet.2022.06.007 35793654 Herrema, H. et al. FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity. Cell Metab. 34 , 1004–1022.e1008 (2022). 35793654 10.1016/j.cmet.2022.06.007

173. Cho YM The IRE1alpha-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARgamma activity Exp. Mol. Med. 2018 50 1 15 10.1038/s12276-018-0131-0 30111834 PMC6093883 Cho, Y. M. et al. The IRE1alpha-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARgamma activity. Exp. Mol. Med. 50 , 1–15 (2018). 30111834 10.1038/s12276-018-0131-0 PMC6093883

174. Wang Z Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARalpha-regulated gene transcription and tumour growth Nat. Cell Biol. 2022 24 1655 1665 10.1038/s41556-022-01009-4 36266488 Wang, Z. et al. Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARalpha-regulated gene transcription and tumour growth. Nat. Cell Biol. 24 , 1655–1665 (2022). 36266488 10.1038/s41556-022-01009-4

175. Zhou J Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress Cell. Mol. Biol. Lett. 2022 27 110 10.1186/s11658-022-00412-x 36526973 PMC9756454 Zhou, J. et al. Metabolic disorders sensitise endometrial carcinoma through endoplasmic reticulum stress. Cell. Mol. Biol. Lett. 27 , 110 (2022). 36526973 10.1186/s11658-022-00412-x PMC9756454

176. Yue J Triphenyl phosphate proved more potent than its metabolite diphenyl phosphate in inducing hepatic insulin resistance through endoplasmic reticulum stress Environ. Int. 2023 172 107749 10.1016/j.envint.2023.107749 36680801 Yue, J. et al. Triphenyl phosphate proved more potent than its metabolite diphenyl phosphate in inducing hepatic insulin resistance through endoplasmic reticulum stress. Environ. Int. 172 , 107749 (2023). 36680801 10.1016/j.envint.2023.107749

177. Yong J Therapeutic opportunities for pancreatic beta-cell ER stress in diabetes mellitus Nat. Rev. Endocrinol. 2021 17 455 467 10.1038/s41574-021-00510-4 34163039 PMC8765009 Yong, J. et al. Therapeutic opportunities for pancreatic beta-cell ER stress in diabetes mellitus. Nat. Rev. Endocrinol. 17 , 455–467 (2021). 34163039 10.1038/s41574-021-00510-4 PMC8765009

178. Park J Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response Nat. Aging 2024 4 839 853 10.1038/s43587-024-00633-z 38858606 PMC11829733 Park, J. et al. Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response. Nat. Aging 4 , 839–853 (2024). 38858606 10.1038/s43587-024-00633-z PMC11829733

179. Lee JN Ye J Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1 J. Biol. Chem. 2004 279 45257 45265 10.1074/jbc.M408235200 15304479 Lee, J. N. & Ye, J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J. Biol. Chem. 279 , 45257–45265 (2004). 15304479 10.1074/jbc.M408235200

180. Liu TF Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis Cell Metab. 2012 16 213 225 10.1016/j.cmet.2012.06.014 22863805 Liu, T. F. et al. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 16 , 213–225 (2012). 22863805 10.1016/j.cmet.2012.06.014

181. Shimano H Sato R SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology Nat. Rev. Endocrinol. 2017 13 710 730 10.1038/nrendo.2017.91 28849786 Shimano, H. & Sato, R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat. Rev. Endocrinol. 13 , 710–730 (2017). 28849786 10.1038/nrendo.2017.91

182. Fuchs CD Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice Hepatology 2022 75 125 139 10.1002/hep.32112 34387896 Fuchs, C. D. et al. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology 75 , 125–139 (2022). 34387896 10.1002/hep.32112

183. Chen Y Adipocyte IRE1alpha promotes PGC1alpha mRNA decay and restrains adaptive thermogenesis Nat. Metab. 2022 4 1166 1184 10.1038/s42255-022-00631-8 36123394 Chen, Y. et al. Adipocyte IRE1alpha promotes PGC1alpha mRNA decay and restrains adaptive thermogenesis. Nat. Metab. 4 , 1166–1184 (2022). 36123394 10.1038/s42255-022-00631-8

184. Zhao G Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids Proc. Natl. Acad. Sci. USA 2022 119 e2203480119 10.1073/pnas.2203480119 36197994 PMC9564215 Zhao, G. et al. Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids. Proc. Natl. Acad. Sci. USA 119 , e2203480119 (2022). 36197994 10.1073/pnas.2203480119 PMC9564215

185. Kim, W. et al. Cellular stress responses in radiotherapy. Cells . 8 , 1105 (2019). 10.3390/cells8091105 PMC6769573 31540530

186. Ala, M. Sestrin2 in cancer: a foe or a friend? Biomark. Res . 10 , 29 (2022). 10.1186/s40364-022-00380-6 PMC9080202 35527284

187. Baek JH PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway Cell Death Dis. 2019 10 156 10.1038/s41419-019-1405-8 30770789 PMC6377650 Baek, J. H. et al. PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway. Cell Death Dis. 10 , 156 (2019). 30770789 10.1038/s41419-019-1405-8 PMC6377650

188. Zhu C CPSF6-mediated XBP1 3’UTR shortening attenuates cisplatin-induced ER stress and elevates chemo-resistance in lung adenocarcinoma Drug Resist. Updat. 2023 68 100933 10.1016/j.drup.2023.100933 36821972 Zhu, C. et al. CPSF6-mediated XBP1 3’UTR shortening attenuates cisplatin-induced ER stress and elevates chemo-resistance in lung adenocarcinoma. Drug Resist. Updat. 68 , 100933 (2023). 36821972 10.1016/j.drup.2023.100933

189. Wong TL ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer Nat. Commun. 2023 14 2861 10.1038/s41467-023-38581-8 37208334 PMC10199093 Wong, T. L. et al. ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer. Nat. Commun. 14 , 2861 (2023). 37208334 10.1038/s41467-023-38581-8 PMC10199093

190. Wu J Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation J. Exp. Clin. Cancer Res. 2018 37 272 10.1186/s13046-018-0935-8 30413206 PMC6230241 Wu, J. et al. Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J. Exp. Clin. Cancer Res. 37 , 272 (2018). 30413206 10.1186/s13046-018-0935-8 PMC6230241

191. Guo B Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2alpha phosphorylation and chemoresistance in colon cancer Cell Death Dis. 2021 12 960 10.1038/s41419-021-04251-0 34663797 PMC8523518 Guo, B. et al. Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2alpha phosphorylation and chemoresistance in colon cancer. Cell Death Dis. 12 , 960 (2021). 34663797 10.1038/s41419-021-04251-0 PMC8523518

192. Chen L LIMK1 m(6)A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation Cancer Lett. 2023 576 216420 10.1016/j.canlet.2023.216420 37778684 Chen, L. et al. LIMK1 m(6)A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation. Cancer Lett. 576 , 216420 (2023). 37778684 10.1016/j.canlet.2023.216420

193. Meacham CE Morrison SJ Tumour heterogeneity and cancer cell plasticity Nature 2013 501 328 337 10.1038/nature12624 24048065 PMC4521623 Meacham, C. E. & Morrison, S. J. Tumour heterogeneity and cancer cell plasticity. Nature 501 , 328–337 (2013). 24048065 10.1038/nature12624 PMC4521623

194. Bhardwaj M Leli NM Koumenis C Amaravadi RK Regulation of autophagy by canonical and non-canonical ER stress responses Semin. Cancer Biol. 2020 66 116 128 10.1016/j.semcancer.2019.11.007 31838023 PMC7325862 Bhardwaj, M., Leli, N. M., Koumenis, C. & Amaravadi, R. K. Regulation of autophagy by canonical and non-canonical ER stress responses. Semin. Cancer Biol. 66 , 116–128 (2020). 31838023 10.1016/j.semcancer.2019.11.007 PMC7325862

195. Uramoto H Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance Lung Cancer 2005 49 55 62 10.1016/j.lungcan.2004.12.011 15949590 Uramoto, H. et al. Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance. Lung Cancer 49 , 55–62 (2005). 15949590 10.1016/j.lungcan.2004.12.011

196. Hu K Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma J. Clin. Invest. 2020 130 1752 1766 10.1172/JCI124049 31874110 PMC7108883 Hu, K. et al. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J. Clin. Invest. 130 , 1752–1766 (2020). 31874110 10.1172/JCI124049 PMC7108883

197. Xu W O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress J. Hepatol. 2017 67 310 320 10.1016/j.jhep.2017.03.017 28347804 Xu, W. et al. O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress. J. Hepatol. 67 , 310–320 (2017). 28347804 10.1016/j.jhep.2017.03.017

198. Im JY CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1alpha-JNK pathways Exp. Mol. Med. 2024 56 235 249 10.1038/s12276-024-01155-9 38253797 PMC10834511 Im, J. Y. et al. CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1alpha-JNK pathways. Exp. Mol. Med. 56 , 235–249 (2024). 38253797 10.1038/s12276-024-01155-9 PMC10834511

199. Zhang LJ Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells Cancer Lett. 2009 274 40 46 10.1016/j.canlet.2008.08.030 18829155 Zhang, L. J. et al. Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells. Cancer Lett. 274 , 40–46 (2009). 18829155 10.1016/j.canlet.2008.08.030

200. Su S Sec62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation Cell Mol. Life Sci. 2022 79 133 10.1007/s00018-022-04143-2 35165763 PMC11073224 Su, S. et al. Sec62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation. Cell Mol. Life Sci. 79 , 133 (2022). 35165763 10.1007/s00018-022-04143-2 PMC11073224

201. Cheng Q SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop J. Exp. Clin. Cancer Res. 2023 42 232 10.1186/s13046-023-02807-w 37670384 PMC10478313 Cheng, Q. et al. SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop. J. Exp. Clin. Cancer Res. 42 , 232 (2023). 37670384 10.1186/s13046-023-02807-w PMC10478313

202. Kuang Y The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin Int. J. Biol. Sci. 2023 19 120 136 10.7150/ijbs.76345 36594085 PMC9760445 Kuang, Y. et al. The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin. Int. J. Biol. Sci. 19 , 120–136 (2023). 36594085 10.7150/ijbs.76345 PMC9760445

203. Guichard C Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells Carcinogenesis 2006 27 1812 1827 10.1093/carcin/bgl009 16524888 Guichard, C. et al. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis 27 , 1812–1827 (2006). 16524888 10.1093/carcin/bgl009

204. Li C Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways J. Exp. Clin. Cancer Res. 2021 40 125 10.1186/s13046-021-01915-9 33838688 PMC8035743 Li, C. et al. Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways. J. Exp. Clin. Cancer Res. 40 , 125 (2021). 33838688 10.1186/s13046-021-01915-9 PMC8035743

205. Lin Z Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer Redox Biol. 2024 75 103286 10.1016/j.redox.2024.103286 39079386 PMC11340627 Lin, Z. et al. Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer. Redox Biol. 75 , 103286 (2024). 39079386 10.1016/j.redox.2024.103286 PMC11340627

206. Chen Y Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress J. Exp. Clin. Cancer Res. 2024 43 261 10.1186/s13046-024-03176-8 39267084 PMC11396530 Chen, Y. et al. Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress. J. Exp. Clin. Cancer Res. 43 , 261 (2024). 39267084 10.1186/s13046-024-03176-8 PMC11396530

207. Shuda M Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis J. Hepatol. 2003 38 605 614 10.1016/S0168-8278(03)00029-1 12713871 Shuda, M. et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J. Hepatol. 38 , 605–614 (2003). 12713871 10.1016/s0168-8278(03)00029-1

208. Hu C Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress J. Exp. Clin. Cancer Res. 2023 42 108 10.1186/s13046-023-02656-7 37122003 PMC10150531 Hu, C. et al. Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. J. Exp. Clin. Cancer Res. 42 , 108 (2023). 37122003 10.1186/s13046-023-02656-7 PMC10150531

209. Yao S Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression J. Biol. Chem. 2014 289 4032 4042 10.1074/jbc.M113.524512 24366867 PMC3924270 Yao, S. et al. Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression. J. Biol. Chem. 289 , 4032–4042 (2014). 24366867 10.1074/jbc.M113.524512 PMC3924270

210. Teng Y FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3beta-Nrf2 signaling Cancer Res. 2017 77 6215 6225 10.1158/0008-5472.CAN-17-2039 28951455 Teng, Y. et al. FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3beta-Nrf2 signaling. Cancer Res. 77 , 6215–6225 (2017). 28951455 10.1158/0008-5472.CAN-17-2039

211. He L HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression Cancer Commun. 2023 43 981 1002 10.1002/cac2.12464 PMC10508155 37405956 He, L. et al. HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression. Cancer Commun. 43 , 981–1002 (2023). 10.1002/cac2.12464 PMC10508155 37405956

212. Arap MA Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands Cancer Cell 2004 6 275 284 10.1016/j.ccr.2004.08.018 15380518 Arap, M. A. et al. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 6 , 275–284 (2004). 15380518 10.1016/j.ccr.2004.08.018

213. Zhou L ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3 Theranostics 2021 11 841 860 10.7150/thno.49384 33391508 PMC7738848 Zhou, L. et al. ACSS3 represses prostate cancer progression through downregulating lipid droplet-associated protein PLIN3. Theranostics 11 , 841–860 (2021). 33391508 10.7150/thno.49384 PMC7738848

214. Pachikov AN The non-canonical mechanism of ER stress-mediated progression of prostate cancer J. Exp. Clin. Cancer Res. 2021 40 289 10.1186/s13046-021-02066-7 34521429 PMC8439065 Pachikov, A. N. et al. The non-canonical mechanism of ER stress-mediated progression of prostate cancer. J. Exp. Clin. Cancer Res. 40 , 289 (2021). 34521429 10.1186/s13046-021-02066-7 PMC8439065

215. Blomme A 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer Nat. Commun. 2020 11 2508 10.1038/s41467-020-16126-7 32427840 PMC7237503 Blomme, A. et al. 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nat. Commun. 11 , 2508 (2020). 32427840 10.1038/s41467-020-16126-7 PMC7237503

216. Marjon, P. L., Bobrovnikova-Marjon, E. V. & Abcouwer, S. F. Expression of the pro-angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 by human breast carcinomas is responsive to nutrient deprivation and endoplasmic reticulum stress. Mol. Cancer . 3 , 4 (2004). 10.1186/1476-4598-3-4 PMC343294 14738568

217. Cook KL Endoplasmic reticulum stress protein GRP78 modulates lipid metabolism to control drug sensitivity and antitumor immunity in breast cancer Cancer Res. 2016 76 5657 5670 10.1158/0008-5472.CAN-15-2616 27698188 PMC5117832 Cook, K. L. et al. Endoplasmic reticulum stress protein GRP78 modulates lipid metabolism to control drug sensitivity and antitumor immunity in breast cancer. Cancer Res. 76 , 5657–5670 (2016). 27698188 10.1158/0008-5472.CAN-15-2616 PMC5117832

218. Harnoss JM IRE1alpha disruption in triple-negative breast cancer cooperates with antiangiogenic therapy by reversing ER stress adaptation and remodeling the tumor microenvironment Cancer Res. 2020 80 2368 2379 10.1158/0008-5472.CAN-19-3108 32265225 PMC7272310 Harnoss, J. M. et al. IRE1alpha disruption in triple-negative breast cancer cooperates with antiangiogenic therapy by reversing ER stress adaptation and remodeling the tumor microenvironment. Cancer Res. 80 , 2368–2379 (2020). 32265225 10.1158/0008-5472.CAN-19-3108 PMC7272310

219. Wang J XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer Cancer Lett. 2024 596 216846 10.1016/j.canlet.2024.216846 38582397 Wang, J. et al. XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer. Cancer Lett. 596 , 216846 (2024). 38582397 10.1016/j.canlet.2024.216846

220. Martin-Perez R Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway Cancer Res. 2014 74 1766 1777 10.1158/0008-5472.CAN-13-1747 24453000 PMC4053205 Martin-Perez, R. et al. Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway. Cancer Res. 74 , 1766–1777 (2014). 24453000 10.1158/0008-5472.CAN-13-1747 PMC4053205

221. Lei P Abdelrahim M Safe S 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways Mol. Cancer Ther. 2006 5 2324 2336 10.1158/1535-7163.MCT-06-0184 16985067 Lei, P., Abdelrahim, M. & Safe, S. 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways. Mol. Cancer Ther. 5 , 2324–2336 (2006). 16985067 10.1158/1535-7163.MCT-06-0184

222. Suarez-Martinez E Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy J. Exp. Clin. Cancer Res. 2024 43 150 10.1186/s13046-024-03071-2 38807192 PMC11134651 Suarez-Martinez, E. et al. Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy. J. Exp. Clin. Cancer Res. 43 , 150 (2024). 38807192 10.1186/s13046-024-03071-2 PMC11134651

223. Li GN Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation Signal Transduct. Target. Ther. 2022 7 317 10.1038/s41392-022-01131-7 36097006 PMC9468165 Li, G. N. et al. Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation. Signal Transduct. Target. Ther. 7 , 317 (2022). 36097006 10.1038/s41392-022-01131-7 PMC9468165

224. Rosati E Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL Blood 2010 116 2713 2723 10.1182/blood-2010-03-275628 20628148 Rosati, E. et al. Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL. Blood 116 , 2713–2723 (2010). 20628148 10.1182/blood-2010-03-275628

225. Maestre L Expression pattern of XBP1(S) in human B-cell lymphomas Haematologica 2009 94 419 422 10.3324/haematol.2008.001156 19176362 PMC2649342 Maestre, L. et al. Expression pattern of XBP1(S) in human B-cell lymphomas. Haematologica 94 , 419–422 (2009). 19176362 10.3324/haematol.2008.001156 PMC2649342

226. Lamothe B Wierda WG Keating MJ Gandhi V Carfilzomib triggers cell death in chronic lymphocytic leukemia by inducing proapoptotic and endoplasmic reticulum stress responses Clin. Cancer Res. 2016 22 4712 4726 10.1158/1078-0432.CCR-15-2522 27026200 PMC5118040 Lamothe, B., Wierda, W. G., Keating, M. J. & Gandhi, V. Carfilzomib triggers cell death in chronic lymphocytic leukemia by inducing proapoptotic and endoplasmic reticulum stress responses. Clin. Cancer Res. 22 , 4712–4726 (2016). 27026200 10.1158/1078-0432.CCR-15-2522 PMC5118040

227. Yanamandra N Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia Clin. Cancer Res. 2006 12 591 599 10.1158/1078-0432.CCR-05-1792 16428505 Yanamandra, N. et al. Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin. Cancer Res. 12 , 591–599 (2006). 16428505 10.1158/1078-0432.CCR-05-1792

228. Philippe C Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy Leukemia 2024 38 1764 1776 10.1038/s41375-024-02321-8 38909090 PMC11286524 Philippe, C. et al. Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy. Leukemia 38 , 1764–1776 (2024). 38909090 10.1038/s41375-024-02321-8 PMC11286524

229. Hernandez-Espinosa D Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment J. Thromb. Haemost. 2009 7 1128 1133 10.1111/j.1538-7836.2009.03449.x 19422445 Hernandez-Espinosa, D. et al. Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment. J. Thromb. Haemost. 7 , 1128–1133 (2009). 19422445 10.1111/j.1538-7836.2009.03449.x

230. Kharabi Masouleh B Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia Proc. Natl. Acad. Sci. USA 2014 111 E2219 E2228 10.1073/pnas.1400958111 24821775 PMC4040579 Kharabi Masouleh, B. et al. Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 111 , E2219–E2228 (2014). 24821775 10.1073/pnas.1400958111 PMC4040579

231. Liu C Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche Theranostics 2022 12 2894 2907 10.7150/thno.67710 35401837 PMC8965499 Liu, C. et al. Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche. Theranostics 12 , 2894–2907 (2022). 35401837 10.7150/thno.67710 PMC8965499

232. Pyrko P The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas Cancer Res. 2007 67 9809 9816 10.1158/0008-5472.CAN-07-0625 17942911 Pyrko, P. et al. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 67 , 9809–9816 (2007). 17942911 10.1158/0008-5472.CAN-07-0625

233. Obacz J IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma Neuro Oncol. 2024 26 858 871 10.1093/neuonc/noad256 38153426 PMC11066906 Obacz, J. et al. IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma. Neuro Oncol. 26 , 858–871 (2024). 38153426 10.1093/neuonc/noad256 PMC11066906

234. Xu H FKBP9 promotes the malignant behavior of glioblastoma cells and confers resistance to endoplasmic reticulum stress inducers J. Exp. Clin. Cancer Res. 2020 39 44 10.1186/s13046-020-1541-0 32111229 PMC7048151 Xu, H. et al. FKBP9 promotes the malignant behavior of glioblastoma cells and confers resistance to endoplasmic reticulum stress inducers. J. Exp. Clin. Cancer Res. 39 , 44 (2020). 32111229 10.1186/s13046-020-1541-0 PMC7048151

235. Li J SelK promotes glioblastoma cell proliferation by inhibiting beta-TrCP1 mediated ubiquitin-dependent degradation of CDK4 J. Exp. Clin. Cancer Res. 2024 43 231 10.1186/s13046-024-03157-x 39155374 PMC11331741 Li, J. et al. SelK promotes glioblastoma cell proliferation by inhibiting beta-TrCP1 mediated ubiquitin-dependent degradation of CDK4. J. Exp. Clin. Cancer Res. 43 , 231 (2024). 39155374 10.1186/s13046-024-03157-x PMC11331741

236. Li, C. et al. Bionanoparticles with in situ nitric oxide release for precise modulation of ER-TRPV1 ion channels in multimodal killing of glioblastoma. Small , 21 , e2408649, (2024). 10.1002/smll.202408649 39587016

237. Jiang CC Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response Cancer Res. 2007 67 5880 5888 10.1158/0008-5472.CAN-07-0213 17575157 Jiang, C. C. et al. Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response. Cancer Res. 67 , 5880–5888 (2007). 17575157 10.1158/0008-5472.CAN-07-0213

238. Luan Q RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy Autophagy 2015 11 975 994 10.1080/15548627.2015.1049800 26018731 PMC4590596 Luan, Q. et al. RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy. Autophagy 11 , 975–994 (2015). 26018731 10.1080/15548627.2015.1049800 PMC4590596

239. Niessner H BRAF inhibitors amplify the proapoptotic activity of MEK inhibitors by inducing ER stress in NRAS-mutant melanoma Clin. Cancer Res. 2017 23 6203 6214 10.1158/1078-0432.CCR-17-0098 28724666 PMC5641247 Niessner, H. et al. BRAF inhibitors amplify the proapoptotic activity of MEK inhibitors by inducing ER stress in NRAS-mutant melanoma. Clin. Cancer Res. 23 , 6203–6214 (2017). 28724666 10.1158/1078-0432.CCR-17-0098 PMC5641247

240. Negorev D Human neutrophils can mimic myeloid-derived suppressor cells (PMN-MDSC) and suppress microbead or lectin-induced T cell proliferation through artefactual mechanisms Sci. Rep. 2018 8 3135 10.1038/s41598-018-21450-6 29453429 PMC5816646 Negorev, D. et al. Human neutrophils can mimic myeloid-derived suppressor cells (PMN-MDSC) and suppress microbead or lectin-induced T cell proliferation through artefactual mechanisms. Sci. Rep. 8 , 3135 (2018). 29453429 10.1038/s41598-018-21450-6 PMC5816646

241. Thevenot PT The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors Immunity 2014 41 389 401 10.1016/j.immuni.2014.08.015 25238096 PMC4171711 Thevenot, P. T. et al. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 41 , 389–401 (2014). 25238096 10.1016/j.immuni.2014.08.015 PMC4171711

242. Zhao Y XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer Signal Transduct. Target. Ther. 2021 6 357 10.1038/s41392-021-00761-7 34667145 PMC8526672 Zhao, Y. et al. XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer. Signal Transduct. Target. Ther. 6 , 357 (2021). 34667145 10.1038/s41392-021-00761-7 PMC8526672

243. Marquez S Endoplasmic reticulum stress sensor IRE1alpha enhances IL-23 expression by human dendritic cells Front. Immunol. 2017 8 639 10.3389/fimmu.2017.00639 28674530 PMC5475432 Marquez, S. et al. Endoplasmic reticulum stress sensor IRE1alpha enhances IL-23 expression by human dendritic cells. Front. Immunol. 8 , 639 (2017). 28674530 10.3389/fimmu.2017.00639 PMC5475432

244. Grivennikov SI Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth Nature 2012 491 254 258 10.1038/nature11465 23034650 PMC3601659 Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491 , 254–258 (2012). 23034650 10.1038/nature11465 PMC3601659

245. Yang, Y. et al. Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A(+) myeloid cells to promote liver cancer progression. Gut. 74 , 255–269 (2024). 10.1136/gutjnl-2024-332429 38981667

246. Gong J UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells Eur. J. Immunol. 2014 44 3758 3767 10.1002/eji.201444574 25209846 Gong, J. et al. UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells. Eur. J. Immunol. 44 , 3758–3767 (2014). 25209846 10.1002/eji.201444574

247. Li, X. et al. Orphan nuclear receptor Nur77 mediates the lethal endoplasmic reticulum stress and therapeutic efficacy of cryptomeridiol in hepatocellular carcinoma. Cells . 11 , 3870 (2022). 10.3390/cells11233870 PMC9737475 36497127

248. Wen H A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway Int. J. Biol. Sci. 2022 18 2898 2913 10.7150/ijbs.70975 35541893 PMC9066120 Wen, H. et al. A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER stress-CHOP pathway. Int. J. Biol. Sci. 18 , 2898–2913 (2022). 35541893 10.7150/ijbs.70975 PMC9066120

249. Liang JJ Design and synthesis of marine sesterterpene analogues as novel estrogen receptor alpha degraders for breast cancer treatment Eur. J. Med. Chem. 2022 229 114081 10.1016/j.ejmech.2021.114081 34992039 Liang, J. J. et al. Design and synthesis of marine sesterterpene analogues as novel estrogen receptor alpha degraders for breast cancer treatment. Eur. J. Med. Chem. 229 , 114081 (2022). 34992039 10.1016/j.ejmech.2021.114081

250. Cubillos-Ruiz JR ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis Cell 2015 161 1527 1538 10.1016/j.cell.2015.05.025 26073941 PMC4580135 Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161 , 1527–1538 (2015). 26073941 10.1016/j.cell.2015.05.025 PMC4580135

251. Cubillos-Ruiz JR Bettigole SE Glimcher LH Molecular pathways: immunosuppressive roles of IRE1alpha-XBP1 signaling in dendritic cells of the tumor microenvironment Clin. Cancer Res. 2016 22 2121 2126 10.1158/1078-0432.CCR-15-1570 26979393 PMC4854763 Cubillos-Ruiz, J. R., Bettigole, S. E. & Glimcher, L. H. Molecular pathways: immunosuppressive roles of IRE1alpha-XBP1 signaling in dendritic cells of the tumor microenvironment. Clin. Cancer Res. 22 , 2121–2126 (2016). 26979393 10.1158/1078-0432.CCR-15-1570 PMC4854763

252. Song M IRE1alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity Nature 2018 562 423 428 10.1038/s41586-018-0597-x 30305738 PMC6237282 Song, M. et al. IRE1alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562 , 423–428 (2018). 30305738 10.1038/s41586-018-0597-x PMC6237282

253. Zhao Y Butler EB Tan M Targeting cellular metabolism to improve cancer therapeutics Cell Death Dis. 2013 4 e532 10.1038/cddis.2013.60 23470539 PMC3613838 Zhao, Y., Butler, E. B. & Tan, M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4 , e532 (2013). 23470539 10.1038/cddis.2013.60 PMC3613838

254. Benetatos L Vartholomatos G Hatzimichael E Polycomb group proteins and MYC: the cancer connection Cell Mol. Life Sci. 2014 71 257 269 10.1007/s00018-013-1426-x 23897499 PMC11113285 Benetatos, L., Vartholomatos, G. & Hatzimichael, E. Polycomb group proteins and MYC: the cancer connection. Cell Mol. Life Sci. 71 , 257–269 (2014). 23897499 10.1007/s00018-013-1426-x PMC11113285

255. Wu CH Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells J. Extracell. Vesicles 2019 8 1588538 10.1080/20013078.2019.1588538 30891164 PMC6419691 Wu, C. H. et al. Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells. J. Extracell. Vesicles 8 , 1588538 (2019). 30891164 10.1080/20013078.2019.1588538 PMC6419691

256. De Leo A Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma Immunity 2024 57 1105 1123.e1108 10.1016/j.immuni.2024.04.006 38703775 PMC11114377 De Leo, A. et al. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity 57 , 1105–1123.e1108 (2024). 38703775 10.1016/j.immuni.2024.04.006 PMC11114377

257. Yang W Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism Nature 2016 531 651 655 10.1038/nature17412 26982734 PMC4851431 Yang, W. et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531 , 651–655 (2016). 26982734 10.1038/nature17412 PMC4851431

258. Raines LN PERK is a critical metabolic hub for immunosuppressive function in macrophages Nat. Immunol. 2022 23 431 445 10.1038/s41590-022-01145-x 35228694 PMC9112288 Raines, L. N. et al. PERK is a critical metabolic hub for immunosuppressive function in macrophages. Nat. Immunol. 23 , 431–445 (2022). 35228694 10.1038/s41590-022-01145-x PMC9112288

259. Obiedat A The integrated stress response promotes B7H6 expression J. Mol. Med. 2020 98 135 148 10.1007/s00109-019-01859-w 31838577 PMC6952340 Obiedat, A. et al. The integrated stress response promotes B7H6 expression. J. Mol. Med. 98 , 135–148 (2020). 31838577 10.1007/s00109-019-01859-w PMC6952340

260. Chakraborty P Carbon monoxide activates PERK-regulated autophagy to induce immunometabolic reprogramming and boost antitumor T-cell function Cancer Res. 2022 82 1969 1990 10.1158/0008-5472.CAN-21-3155 35404405 PMC9117468 Chakraborty, P. et al. Carbon monoxide activates PERK-regulated autophagy to induce immunometabolic reprogramming and boost antitumor T-cell function. Cancer Res. 82 , 1969–1990 (2022). 35404405 10.1158/0008-5472.CAN-21-3155 PMC9117468

261. Jurgens CY State of the science: the relevance of symptoms in cardiovascular disease and research: a scientific statement from the American Heart Association Circulation 2022 146 e173 e184 10.1161/CIR.0000000000001089 35979825 Jurgens, C. Y. et al. State of the science: the relevance of symptoms in cardiovascular disease and research: a scientific statement from the American Heart Association. Circulation 146 , e173–e184 (2022). 35979825 10.1161/CIR.0000000000001089

262. Zhang Y Murugesan P Huang K Cai H NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets Nat. Rev. Cardiol. 2020 17 170 194 10.1038/s41569-019-0260-8 31591535 PMC7880919 Zhang, Y., Murugesan, P., Huang, K. & Cai, H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat. Rev. Cardiol. 17 , 170–194 (2020). 31591535 10.1038/s41569-019-0260-8 PMC7880919

263. Kong P Inflammation and atherosclerosis: signaling pathways and therapeutic intervention Signal Transduct. Target. Ther. 2022 7 131 10.1038/s41392-022-00955-7 35459215 PMC9033871 Kong, P. et al. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct. Target. Ther. 7 , 131 (2022). 35459215 10.1038/s41392-022-00955-7 PMC9033871

264. Nonaka H Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine Circulation 2001 104 1165 1170 10.1161/hc3601.093976 11535574 Nonaka, H. et al. Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine. Circulation 104 , 1165–1170 (2001). 11535574 10.1161/hc3601.093976

265. Yildirim Z Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression EMBO Mol. Med. 2022 14 e15344 10.15252/emmm.202115344 35191199 PMC8988208 Yildirim, Z. et al. Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO Mol. Med. 14 , e15344 (2022). 35191199 10.15252/emmm.202115344 PMC8988208

266. Cai Z Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals Arterioscler. Thromb. Vasc. Biol. 2013 33 2345 2354 10.1161/ATVBAHA.112.300226 23928865 Cai, Z. et al. Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals. Arterioscler. Thromb. Vasc. Biol. 33 , 2345–2354 (2013). 23928865 10.1161/ATVBAHA.112.300226

267. Boutagy, N. E. et al. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. J. Clin. Invest . 134 , e170453 (2024). 10.1172/JCI170453 PMC10866653 38175710

268. Lin H Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching Int. J. Cardiol. 2018 269 242 249 10.1016/j.ijcard.2018.07.043 30017525 Lin, H. et al. Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching. Int. J. Cardiol. 269 , 242–249 (2018). 30017525 10.1016/j.ijcard.2018.07.043

269. Zahid MDK CCAAT/enhancer-binding protein beta (C/EBPbeta) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells Mol. Cell Biochem. 2020 463 211 223 10.1007/s11010-019-03642-4 31686316 Zahid, M. D. K. et al. CCAAT/enhancer-binding protein beta (C/EBPbeta) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells. Mol. Cell Biochem. 463 , 211–223 (2020). 31686316 10.1007/s11010-019-03642-4

270. Abe, J. I. et al. MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. JCI Insight 4 , e125570 (2019). 10.1172/jci.insight.125570 PMC6483653 30944250

271. Zeng L Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow Proc. Natl. Acad. Sci. USA 2009 106 8326 8331 10.1073/pnas.0903197106 19416856 PMC2676169 Zeng, L. et al. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc. Natl. Acad. Sci. USA 106 , 8326–8331 (2009). 19416856 10.1073/pnas.0903197106 PMC2676169

272. Yang MY Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells Acta Pharmacol. Sin. 2018 39 48 58 10.1038/aps.2017.81 28858301 PMC5758670 Yang, M. Y. et al. Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells. Acta Pharmacol. Sin. 39 , 48–58 (2018). 28858301 10.1038/aps.2017.81 PMC5758670

273. Kaw K Smooth muscle alpha-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells Eur. Heart J. 2023 44 2713 2726 10.1093/eurheartj/ehad373 37377039 PMC10393072 Kaw, K. et al. Smooth muscle alpha-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells. Eur. Heart J. 44 , 2713–2726 (2023). 37377039 10.1093/eurheartj/ehad373 PMC10393072

274. Myoishi M Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome Circulation 2007 116 1226 1233 10.1161/CIRCULATIONAHA.106.682054 17709641 Myoishi, M. et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116 , 1226–1233 (2007). 17709641 10.1161/CIRCULATIONAHA.106.682054

275. Liu J Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway Int. J. Mol. Med. 2020 46 1671 1682 33000267 10.3892/ijmm.2020.4728 PMC7521546 Liu, J. et al. Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway. Int. J. Mol. Med. 46 , 1671–1682 (2020). 33000267 10.3892/ijmm.2020.4728 PMC7521546

276. Martindale JJ Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6 Circ. Res. 2006 98 1186 1193 10.1161/01.RES.0000220643.65941.8d 16601230 Martindale, J. J. et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ. Res. 98 , 1186–1193 (2006). 16601230 10.1161/01.RES.0000220643.65941.8d

277. Yang K Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition Eur. Heart J. 2024 45 1662 1680 10.1093/eurheartj/ehae205 38666340 PMC11089336 Yang, K. et al. Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition. Eur. Heart J. 45 , 1662–1680 (2024). 38666340 10.1093/eurheartj/ehae205 PMC11089336

278. Chen J Estrogen inhibits endoplasmic reticulum stress and ameliorates myocardial ischemia/reperfusion injury in rats by upregulating SERCA2a Cell Commun. Signal. 2022 20 38 10.1186/s12964-022-00842-2 35331264 PMC8944077 Chen, J. et al. Estrogen inhibits endoplasmic reticulum stress and ameliorates myocardial ischemia/reperfusion injury in rats by upregulating SERCA2a. Cell Commun. Signal. 20 , 38 (2022). 35331264 10.1186/s12964-022-00842-2 PMC8944077

279. Blackwood EA Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis Nat. Commun. 2019 10 187 10.1038/s41467-018-08129-2 30643122 PMC6331617 Blackwood, E. A. et al. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat. Commun. 10 , 187 (2019). 30643122 10.1038/s41467-018-08129-2 PMC6331617

280. Reed GW Rossi JE Cannon CP Acute myocardial infarction Lancet 2017 389 197 210 10.1016/S0140-6736(16)30677-8 27502078 Reed, G. W., Rossi, J. E. & Cannon, C. P. Acute myocardial infarction. Lancet 389 , 197–210 (2017). 27502078 10.1016/S0140-6736(16)30677-8

281. Groenendyk J Agellon LB Michalak M Coping with endoplasmic reticulum stress in the cardiovascular system Annu. Rev. Physiol. 2013 75 49 67 10.1146/annurev-physiol-030212-183707 23020580 Groenendyk, J., Agellon, L. B. & Michalak, M. Coping with endoplasmic reticulum stress in the cardiovascular system. Annu. Rev. Physiol. 75 , 49–67 (2013). 23020580 10.1146/annurev-physiol-030212-183707

282. Thuerauf DJ Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes Circ. Res. 2006 99 275 282 10.1161/01.RES.0000233317.70421.03 16794188 Thuerauf, D. J. et al. Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ. Res. 99 , 275–282 (2006). 16794188 10.1161/01.RES.0000233317.70421.03

283. Liu, M. et al. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction. J. Clin. Invest . 131 , e147836 (2021). 10.1172/JCI147836 PMC8439592 34324437

284. Liu M Kang GJ Dudley SC Jr Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias Trends Mol. Med. 2022 28 443 451 10.1016/j.molmed.2022.03.006 35414478 PMC9149111 Liu, M., Kang, G. J. & Dudley, S. C. Jr Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias. Trends Mol. Med. 28 , 443–451 (2022). 35414478 10.1016/j.molmed.2022.03.006 PMC9149111

285. Liu M Panax quinquefolium saponin attenuates ventricular remodeling after acute myocardial infarction by inhibiting chop-mediated apoptosis Shock 2013 40 339 344 10.1097/SHK.0b013e3182a3f9e5 23856922 Liu, M. et al. Panax quinquefolium saponin attenuates ventricular remodeling after acute myocardial infarction by inhibiting chop-mediated apoptosis. Shock 40 , 339–344 (2013). 23856922 10.1097/SHK.0b013e3182a3f9e5

286. Mali V Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes Pflug. Arch. 2018 470 471 480 10.1007/s00424-017-2097-5 29288332 Mali, V. et al. Essential role for EGFR tyrosine kinase and ER stress in myocardial infarction in type 2 diabetes. Pflug. Arch. 470 , 471–480 (2018). 10.1007/s00424-017-2097-5 29288332

287. Toko H ATF6 is important under both pathological and physiological states in the heart J. Mol. Cell Cardiol. 2010 49 113 120 10.1016/j.yjmcc.2010.03.020 20380836 Toko, H. et al. ATF6 is important under both pathological and physiological states in the heart. J. Mol. Cell Cardiol. 49 , 113–120 (2010). 20380836 10.1016/j.yjmcc.2010.03.020

288. Glembotski CC Rosarda JD Wiseman RL Proteostasis and beyond: ATF6 in ischemic disease Trends Mol. Med. 2019 25 538 550 10.1016/j.molmed.2019.03.005 31078432 PMC6592750 Glembotski, C. C., Rosarda, J. D. & Wiseman, R. L. Proteostasis and beyond: ATF6 in ischemic disease. Trends Mol. Med. 25 , 538–550 (2019). 31078432 10.1016/j.molmed.2019.03.005 PMC6592750

289. Prola A SIRT1 protects the heart from ER stress-induced cell death through eIF2alpha deacetylation Cell Death Differ. 2017 24 343 356 10.1038/cdd.2016.138 27911441 PMC5299716 Prola, A. et al. SIRT1 protects the heart from ER stress-induced cell death through eIF2alpha deacetylation. Cell Death Differ. 24 , 343–356 (2017). 27911441 10.1038/cdd.2016.138 PMC5299716

290. Steiger D The serine/threonine-protein kinase/endoribonuclease IRE1alpha protects the heart against pressure overload-induced heart failure J. Biol. Chem. 2018 293 9652 9661 10.1074/jbc.RA118.003448 29769316 PMC6016466 Steiger, D. et al. The serine/threonine-protein kinase/endoribonuclease IRE1alpha protects the heart against pressure overload-induced heart failure. J. Biol. Chem. 293 , 9652–9661 (2018). 29769316 10.1074/jbc.RA118.003448 PMC6016466

291. Binder P Pak2 as a novel therapeutic target for cardioprotective endoplasmic reticulum stress response Circ. Res. 2019 124 696 711 10.1161/CIRCRESAHA.118.312829 30620686 PMC6407830 Binder, P. et al. Pak2 as a novel therapeutic target for cardioprotective endoplasmic reticulum stress response. Circ. Res. 124 , 696–711 (2019). 30620686 10.1161/CIRCRESAHA.118.312829 PMC6407830

292. Gao G Unfolded protein response regulates cardiac sodium current in systolic human heart failure Circ. Arrhythm. Electrophysiol. 2013 6 1018 1024 10.1161/CIRCEP.113.000274 24036084 PMC3909518 Gao, G. et al. Unfolded protein response regulates cardiac sodium current in systolic human heart failure. Circ. Arrhythm. Electrophysiol. 6 , 1018–1024 (2013). 24036084 10.1161/CIRCEP.113.000274 PMC3909518

293. Yao Y A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure Nat. Commun. 2017 8 133 10.1038/s41467-017-00171-w 28743963 PMC5527107 Yao, Y. et al. A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure. Nat. Commun. 8 , 133 (2017). 28743963 10.1038/s41467-017-00171-w PMC5527107

294. Song XJ Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response Int J. Med. Sci. 2011 8 564 572 10.7150/ijms.8.564 21960749 PMC3180773 Song, X. J. et al. Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response. Int J. Med. Sci. 8 , 564–572 (2011). 21960749 10.7150/ijms.8.564 PMC3180773

295. Prola A Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes Cardiovasc Res. 2019 115 328 342 10.1093/cvr/cvy197 30084984 Prola, A. et al. Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes. Cardiovasc Res. 115 , 328–342 (2019). 30084984 10.1093/cvr/cvy197

296. Zhao A Role of histone modifications in neurogenesis and neurodegenerative disease development Ageing Res. Rev. 2024 98 102324 10.1016/j.arr.2024.102324 38762100 Zhao, A. et al. Role of histone modifications in neurogenesis and neurodegenerative disease development. Ageing Res. Rev. 98 , 102324 (2024). 38762100 10.1016/j.arr.2024.102324

297. Chen W Maprotiline restores ER homeostasis and rescues neurodegeneration via histamine receptor H1 inhibition in retinal ganglion cells Nat. Commun. 2022 13 6796 10.1038/s41467-022-34682-y 36357388 PMC9649812 Chen, W. et al. Maprotiline restores ER homeostasis and rescues neurodegeneration via histamine receptor H1 inhibition in retinal ganglion cells. Nat. Commun. 13 , 6796 (2022). 36357388 10.1038/s41467-022-34682-y PMC9649812

298. Ossenkoppele R van der Kant R Hansson O Tau biomarkers in Alzheimer’s disease: towards implementation in clinical practice and trials Lancet Neurol. 2022 21 726 734 10.1016/S1474-4422(22)00168-5 35643092 Ossenkoppele, R., van der Kant, R. & Hansson, O. Tau biomarkers in Alzheimer’s disease: towards implementation in clinical practice and trials. Lancet Neurol. 21 , 726–734 (2022). 35643092 10.1016/S1474-4422(22)00168-5

299. Chiti F Dobson CM Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade Annu. Rev. Biochem 2017 86 27 68 10.1146/annurev-biochem-061516-045115 28498720 Chiti, F. & Dobson, C. M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem 86 , 27–68 (2017). 28498720 10.1146/annurev-biochem-061516-045115

300. Lee JH Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice Exp. Mol. Med. 2010 42 386 394 10.3858/emm.2010.42.5.040 20368688 PMC2877248 Lee, J. H. et al. Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice. Exp. Mol. Med. 42 , 386–394 (2010). 20368688 10.3858/emm.2010.42.5.040 PMC2877248

301. Duran-Aniotz C The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis Mol. Ther. 2023 31 2240 2256 10.1016/j.ymthe.2023.03.028 37016577 PMC10362463 Duran-Aniotz, C. et al. The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis. Mol. Ther. 31 , 2240–2256 (2023). 37016577 10.1016/j.ymthe.2023.03.028 PMC10362463

302. Hoozemans JJ The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus Am. J. Pathol. 2009 174 1241 1251 10.2353/ajpath.2009.080814 19264902 PMC2671357 Hoozemans, J. J. et al. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am. J. Pathol. 174 , 1241–1251 (2009). 19264902 10.2353/ajpath.2009.080814 PMC2671357

303. Yang W Repression of the eIF2alpha kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease Neurobiol. Aging 2016 41 19 24 10.1016/j.neurobiolaging.2016.02.005 27103515 PMC4841914 Yang, W. et al. Repression of the eIF2alpha kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease. Neurobiol. Aging 41 , 19–24 (2016). 27103515 10.1016/j.neurobiolaging.2016.02.005 PMC4841914

304. Kumar A 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience Neuron 2023 111 2831 2846.e2810 10.1016/j.neuron.2023.06.013 37453419 PMC10528360 Kumar, A. et al. 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience. Neuron 111 , 2831–2846.e2810 (2023). 37453419 10.1016/j.neuron.2023.06.013 PMC10528360

305. Baleriola J Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions Cell 2014 158 1159 1172 10.1016/j.cell.2014.07.001 25171414 PMC4149755 Baleriola, J. et al. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158 , 1159–1172 (2014). 25171414 10.1016/j.cell.2014.07.001 PMC4149755

306. Bloem BR Okun MS Klein C Parkinson’s disease Lancet 2021 397 2284 2303 10.1016/S0140-6736(21)00218-X 33848468 Bloem, B. R., Okun, M. S. & Klein, C. Parkinson’s disease. Lancet 397 , 2284–2303 (2021). 33848468 10.1016/S0140-6736(21)00218-X

307. Chun HS Lee H Son JH Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741 Neurosci. Lett. 2001 316 5 8 10.1016/S0304-3940(01)02341-2 11720765 Chun, H. S., Lee, H. & Son, J. H. Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741. Neurosci. Lett. 316 , 5–8 (2001). 11720765 10.1016/s0304-3940(01)02341-2

308. Fouillet A ER stress inhibits neuronal death by promoting autophagy Autophagy 2012 8 915 926 10.4161/auto.19716 22660271 PMC3427257 Fouillet, A. et al. ER stress inhibits neuronal death by promoting autophagy. Autophagy 8 , 915–926 (2012). 22660271 10.4161/auto.19716 PMC3427257

309. Zeng XS The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease Free Radic. Biol. Med. 2014 67 10 18 10.1016/j.freeradbiomed.2013.10.013 24140863 Zeng, X. S. et al. The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radic. Biol. Med. 67 , 10–18 (2014). 24140863 10.1016/j.freeradbiomed.2013.10.013

310. Zeng X Thioredoxin-1 inhibits the activation of IRE1 by targeting Hsp90/p-Cdc37 chaperone complex in Parkinson disease Ageing Res. Rev. 2023 90 102000 10.1016/j.arr.2023.102000 37437766 Zeng, X. et al. Thioredoxin-1 inhibits the activation of IRE1 by targeting Hsp90/p-Cdc37 chaperone complex in Parkinson disease. Ageing Res. Rev. 90 , 102000 (2023). 37437766 10.1016/j.arr.2023.102000

311. El Manaa W Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology Autophagy 2021 17 4363 4385 10.1080/15548627.2021.1917129 34030589 PMC8726674 El Manaa, W. et al. Transcription- and phosphorylation-dependent control of a functional interplay between XBP1s and PINK1 governs mitophagy and potentially impacts Parkinson disease pathophysiology. Autophagy 17 , 4363–4385 (2021). 34030589 10.1080/15548627.2021.1917129 PMC8726674

312. Menozzi E Toffoli M Schapira AHV Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues Pharmacol. Ther. 2023 246 108419 10.1016/j.pharmthera.2023.108419 37080432 Menozzi, E., Toffoli, M. & Schapira, A. H. V. Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues. Pharmacol. Ther. 246 , 108419 (2023). 37080432 10.1016/j.pharmthera.2023.108419

313. Credle JJ alpha-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson’s disease Neurobiol. Dis. 2015 76 112 125 10.1016/j.nbd.2015.02.005 25725420 Credle, J. J. et al. alpha-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson’s disease. Neurobiol. Dis. 76 , 112–125 (2015). 25725420 10.1016/j.nbd.2015.02.005

314. Lee JH Parkinson’s disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes Acta Neuropathol. Commun. 2019 7 68 10.1186/s40478-019-0716-4 31046837 PMC6498585 Lee, J. H. et al. Parkinson’s disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. Acta Neuropathol. Commun. 7 , 68 (2019). 31046837 10.1186/s40478-019-0716-4 PMC6498585

315. Yao L LRRK2 Gly2019Ser mutation promotes ER stress via interacting with THBS1/TGF-beta1 in Parkinson’s disease Adv. Sci. 2023 10 e2303711 10.1002/advs.202303711 PMC10602550 37672887 Yao, L. et al. LRRK2 Gly2019Ser mutation promotes ER stress via interacting with THBS1/TGF-beta1 in Parkinson’s disease. Adv. Sci. 10 , e2303711 (2023). 10.1002/advs.202303711 PMC10602550 37672887

316. Tabrizi SJ A biological classification of Huntington’s disease: the Integrated Staging System Lancet Neurol. 2022 21 632 644 10.1016/S1474-4422(22)00120-X 35716693 Tabrizi, S. J. et al. A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol. 21 , 632–644 (2022). 35716693 10.1016/S1474-4422(22)00120-X

317. Walker FO Huntington’s disease Lancet 2007 369 218 228 10.1016/S0140-6736(07)60111-1 17240289 Walker, F. O. Huntington’s disease. Lancet 369 , 218–228 (2007). 17240289 10.1016/S0140-6736(07)60111-1

318. Nishitoh H ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats Genes Dev. 2002 16 1345 1355 10.1101/gad.992302 12050113 PMC186318 Nishitoh, H. et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16 , 1345–1355 (2002). 12050113 10.1101/gad.992302 PMC186318

319. Hyrskyluoto A Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1alpha Hum. Mol. Genet. 2014 23 5928 5939 10.1093/hmg/ddu317 24951540 Hyrskyluoto, A. et al. Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1alpha. Hum. Mol. Genet. 23 , 5928–5939 (2014). 24951540 10.1093/hmg/ddu317

320. Vidal RL Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy Hum. Mol. Genet. 2012 21 2245 2262 10.1093/hmg/dds040 22337954 PMC3335312 Vidal, R. L. et al. Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum. Mol. Genet. 21 , 2245–2262 (2012). 22337954 10.1093/hmg/dds040 PMC3335312

321. El-Daher MT Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation EMBO J. 2015 34 2255 2271 10.15252/embj.201490808 26165689 PMC4585462 El-Daher, M. T. et al. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 34 , 2255–2271 (2015). 26165689 10.15252/embj.201490808 PMC4585462

322. Naranjo JR Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease J. Clin. Invest. 2016 126 627 638 10.1172/JCI82670 26752648 PMC4731176 Naranjo, J. R. et al. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. J. Clin. Invest. 126 , 627–638 (2016). 26752648 10.1172/JCI82670 PMC4731176

323. Liu Y Endoplasmic reticulum stress in diseases MedComm 2024 5 e701 10.1002/mco2.701 39188936 PMC11345536 Liu, Y. et al. Endoplasmic reticulum stress in diseases. MedComm 5 , e701 (2024). (2020) . 39188936 10.1002/mco2.701 PMC11345536

324. Tang Q Li Y He J MANF: an emerging therapeutic target for metabolic diseases Trends Endocrinol. Metab. 2022 33 236 246 10.1016/j.tem.2022.01.001 35135706 Tang, Q., Li, Y. & He, J. MANF: an emerging therapeutic target for metabolic diseases. Trends Endocrinol. Metab. 33 , 236–246 (2022). 35135706 10.1016/j.tem.2022.01.001

325. Yang Q Vijayakumar A Kahn BB Metabolites as regulators of insulin sensitivity and metabolism Nat. Rev. Mol. Cell Biol. 2018 19 654 672 10.1038/s41580-018-0044-8 30104701 PMC6380503 Yang, Q., Vijayakumar, A. & Kahn, B. B. Metabolites as regulators of insulin sensitivity and metabolism. Nat. Rev. Mol. Cell Biol. 19 , 654–672 (2018). 30104701 10.1038/s41580-018-0044-8 PMC6380503

326. Salvado L Palomer X Barroso E Vazquez-Carrera M Targeting endoplasmic reticulum stress in insulin resistance Trends Endocrinol. Metab. 2015 26 438 448 10.1016/j.tem.2015.05.007 26078196 Salvado, L., Palomer, X., Barroso, E. & Vazquez-Carrera, M. Targeting endoplasmic reticulum stress in insulin resistance. Trends Endocrinol. Metab. 26 , 438–448 (2015). 26078196 10.1016/j.tem.2015.05.007

327. Suzuki T ER stress protein CHOP mediates insulin resistance by modulating adipose tissue macrophage polarity Cell Rep. 2017 18 2045 2057 10.1016/j.celrep.2017.01.076 28228268 Suzuki, T. et al. ER stress protein CHOP mediates insulin resistance by modulating adipose tissue macrophage polarity. Cell Rep. 18 , 2045–2057 (2017). 28228268 10.1016/j.celrep.2017.01.076

328. Abdollahi M miR-379 mediates insulin resistance and obesity through impaired angiogenesis and adipogenesis regulated by ER stress Mol. Ther. Nucleic Acids 2022 30 115 130 10.1016/j.omtn.2022.09.015 36250205 PMC9535382 Abdollahi, M. et al. miR-379 mediates insulin resistance and obesity through impaired angiogenesis and adipogenesis regulated by ER stress. Mol. Ther. Nucleic Acids 30 , 115–130 (2022). 36250205 10.1016/j.omtn.2022.09.015 PMC9535382

329. Cha HN Woo CH Kim HY Park SY Methionine sulfoxide reductase B3 deficiency inhibits the development of diet-induced insulin resistance in mice Redox Biol. 2021 38 101823 10.1016/j.redox.2020.101823 33296856 PMC8187883 Cha, H. N., Woo, C. H., Kim, H. Y. & Park, S. Y. Methionine sulfoxide reductase B3 deficiency inhibits the development of diet-induced insulin resistance in mice. Redox Biol. 38 , 101823 (2021). 33296856 10.1016/j.redox.2020.101823 PMC8187883

330. Crawford AL Laiteerapong N Type 2 diabetes Ann. Intern. Med. 2024 177 ITC81 ITC96 10.7326/AITC202406180 38857502 Crawford, A. L. & Laiteerapong, N. Type 2 diabetes. Ann. Intern. Med. 177 , ITC81–ITC96 (2024). 38857502 10.7326/AITC202406180

331. Xourafa G Korbmacher M Roden M Inter-organ crosstalk during development and progression of type 2 diabetes mellitus Nat. Rev. Endocrinol. 2024 20 27 49 10.1038/s41574-023-00898-1 37845351 Xourafa, G., Korbmacher, M. & Roden, M. Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 20 , 27–49 (2024). 37845351 10.1038/s41574-023-00898-1

332. Harding HP Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival Mol. Cell 2001 7 1153 1163 10.1016/S1097-2765(01)00264-7 11430819 Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol. Cell 7 , 1153–1163 (2001). 11430819 10.1016/s1097-2765(01)00264-7

333. Nie X Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARdelta-Dependent mechanism Redox Biol. 2020 37 101728 10.1016/j.redox.2020.101728 32961442 PMC7509074 Nie, X. et al. Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARdelta-Dependent mechanism. Redox Biol. 37 , 101728 (2020). 32961442 10.1016/j.redox.2020.101728 PMC7509074

334. Luo H Down-regulation of AMPK/PPARdelta signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes Cardiovasc Res. 2022 118 2304 2316 10.1093/cvr/cvab280 34415333 PMC9890455 Luo, H. et al. Down-regulation of AMPK/PPARdelta signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes. Cardiovasc Res. 118 , 2304–2316 (2022). 34415333 10.1093/cvr/cvab280 PMC9890455

335. Yalcinkaya M HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic beta-cells in vitro by activation of Smoothened J. Lipid Res. 2020 61 492 504 10.1194/jlr.RA119000509 31907205 PMC7112150 Yalcinkaya, M. et al. HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic beta-cells in vitro by activation of Smoothened. J. Lipid Res. 61 , 492–504 (2020). 31907205 10.1194/jlr.RA119000509 PMC7112150

336. Zhang Z Swimming differentially affects T2DM-induced skeletal muscle ER stress and mitochondrial dysfunction related to MAM Diabetes Metab. Syndr. Obes. 2020 13 1417 1428 10.2147/DMSO.S243024 32431525 PMC7203063 Zhang, Z. et al. Swimming differentially affects T2DM-induced skeletal muscle ER stress and mitochondrial dysfunction related to MAM. Diabetes Metab. Syndr. Obes. 13 , 1417–1428 (2020). 32431525 10.2147/DMSO.S243024 PMC7203063

337. Oyadomari S Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes J. Clin. Invest. 2002 109 525 532 10.1172/JCI0214550 11854325 PMC150879 Oyadomari, S. et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Invest. 109 , 525–532 (2002). 11854325 10.1172/JCI14550 PMC150879

338. Laybutt DR Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes Diabetologia 2007 50 752 763 10.1007/s00125-006-0590-z 17268797 Laybutt, D. R. et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50 , 752–763 (2007). 17268797 10.1007/s00125-006-0590-z

339. Cho, J. A. et al. Exercise and curcumin in combination improves cognitive function and attenuates ER stress in diabetic rats. Nutrients . 12 , 1309 (2020). 10.3390/nu12051309 PMC7284733 32375323

340. Zhang Y THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic beta-cell function and preserving beta-cell mass Nat. Commun. 2023 14 1020 10.1038/s41467-023-36680-0 36823211 PMC9950491 Zhang, Y. et al. THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic beta-cell function and preserving beta-cell mass. Nat. Commun. 14 , 1020 (2023). 36823211 10.1038/s41467-023-36680-0 PMC9950491

341. Gupta S McGrath B Cavener DR PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway Diabetes 2010 59 1937 1947 10.2337/db09-1064 20530744 PMC2911049 Gupta, S., McGrath, B. & Cavener, D. R. PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59 , 1937–1947 (2010). 20530744 10.2337/db09-1064 PMC2911049

342. Huang Q Selenium nanodots (SENDs) as antioxidants and antioxidant-prodrugs to rescue islet beta cells in type 2 diabetes mellitus by restoring mitophagy and alleviating endoplasmic reticulum stress Adv. Sci. 2023 10 e2300880 10.1002/advs.202300880 PMC10323656 37408520 Huang, Q. et al. Selenium nanodots (SENDs) as antioxidants and antioxidant-prodrugs to rescue islet beta cells in type 2 diabetes mellitus by restoring mitophagy and alleviating endoplasmic reticulum stress. Adv. Sci. 10 , e2300880 (2023). 10.1002/advs.202300880 PMC10323656 37408520

343. Piche ME Tchernof A Despres JP Obesity phenotypes, diabetes, and cardiovascular diseases Circ. Res. 2020 126 1477 1500 10.1161/CIRCRESAHA.120.316101 32437302 Piche, M. E., Tchernof, A. & Despres, J. P. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ. Res. 126 , 1477–1500 (2020). 32437302 10.1161/CIRCRESAHA.120.316101

344. Shan B The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity Nat. Immunol. 2017 18 519 529 10.1038/ni.3709 28346409 Shan, B. et al. The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat. Immunol. 18 , 519–529 (2017). 28346409 10.1038/ni.3709

345. Friedman JM Leptin and the endocrine control of energy balance Nat. Metab. 2019 1 754 764 10.1038/s42255-019-0095-y 32694767 Friedman, J. M. Leptin and the endocrine control of energy balance. Nat. Metab. 1 , 754–764 (2019). 32694767 10.1038/s42255-019-0095-y

346. Park S Aintablian A Coupe B Bouret SG The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates Nat. Commun. 2020 11 1914 10.1038/s41467-020-15624-y 32313051 PMC7171135 Park, S., Aintablian, A., Coupe, B. & Bouret, S. G. The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates. Nat. Commun. 11 , 1914 (2020). 32313051 10.1038/s41467-020-15624-y PMC7171135

347. Lopez-Domenech S Moderate weight loss attenuates chronic endoplasmic reticulum stress and mitochondrial dysfunction in human obesity Mol. Metab. 2019 19 24 33 10.1016/j.molmet.2018.10.005 30385096 PMC6323177 Lopez-Domenech, S. et al. Moderate weight loss attenuates chronic endoplasmic reticulum stress and mitochondrial dysfunction in human obesity. Mol. Metab. 19 , 24–33 (2019). 30385096 10.1016/j.molmet.2018.10.005 PMC6323177

348. Vega-Martin E Impact of caloric restriction on AMPK and endoplasmic reticulum stress in peripheral tissues and circulating peripheral blood mononuclear cells from Zucker rats J. Nutr. Biochem. 2020 78 108342 10.1016/j.jnutbio.2020.108342 32004927 Vega-Martin, E. et al. Impact of caloric restriction on AMPK and endoplasmic reticulum stress in peripheral tissues and circulating peripheral blood mononuclear cells from Zucker rats. J. Nutr. Biochem. 78 , 108342 (2020). 32004927 10.1016/j.jnutbio.2020.108342

349. Xiao ZX Miller JS Zheng SG An updated advance of autoantibodies in autoimmune diseases Autoimmun. Rev. 2021 20 102743 10.1016/j.autrev.2020.102743 33333232 Xiao, Z. X., Miller, J. S. & Zheng, S. G. An updated advance of autoantibodies in autoimmune diseases. Autoimmun. Rev. 20 , 102743 (2021). 33333232 10.1016/j.autrev.2020.102743

350. Li G Breaking boundaries: chronic diseases and the frontiers of immune microenvironments Med. Res. 2025 1 62 102 Li, G. et al. Breaking boundaries: chronic diseases and the frontiers of immune microenvironments. Med. Res. 1 , 62–102 (2025).

351. Fugger L Jensen LT Rossjohn J Challenges, progress, and prospects of developing therapies to treat autoimmune diseases Cell 2020 181 63 80 10.1016/j.cell.2020.03.007 32243797 Fugger, L., Jensen, L. T. & Rossjohn, J. Challenges, progress, and prospects of developing therapies to treat autoimmune diseases. Cell 181 , 63–80 (2020). 32243797 10.1016/j.cell.2020.03.007

352. Smolen JS Aletaha D McInnes IB Rheumatoid arthritis Lancet 2016 388 2023 2038 10.1016/S0140-6736(16)30173-8 27156434 Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388 , 2023–2038 (2016). 27156434 10.1016/S0140-6736(16)30173-8

353. Miglioranza Scavuzzi, B. & Holoshitz, J. Endoplasmic reticulum stress, oxidative stress, and rheumatic diseases. Antioxidants 11 , 1306 (2022). 10.3390/antiox11071306 PMC9312221 35883795

354. Qi W Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage Mater. Today Bio 2023 21 100702 10.1016/j.mtbio.2023.100702 37408696 PMC10319325 Qi, W. et al. Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage. Mater. Today Bio 21 , 100702 (2023). 37408696 10.1016/j.mtbio.2023.100702 PMC10319325

355. Savic S TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes J. Autoimmun. 2014 50 59 66 10.1016/j.jaut.2013.11.002 24387801 PMC4012140 Savic, S. et al. TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes. J. Autoimmun. 50 , 59–66 (2014). 24387801 10.1016/j.jaut.2013.11.002 PMC4012140

356. Hu F Endoplasmic reticulum stress perpetuated toll-like receptor signalling-mediated inflammation in rheumatoid arthritis via X-box-binding protein-1 Clin. Exp. Rheumatol. 2021 39 859 867 10.55563/clinexprheumatol/a7ehz7 32896245 Hu, F. et al. Endoplasmic reticulum stress perpetuated toll-like receptor signalling-mediated inflammation in rheumatoid arthritis via X-box-binding protein-1. Clin. Exp. Rheumatol. 39 , 859–867 (2021). 32896245

357. Geng M Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis Clin. Immunol. 2020 220 108579 10.1016/j.clim.2020.108579 32866644 Geng, M. et al. Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis. Clin. Immunol. 220 , 108579 (2020). 32866644 10.1016/j.clim.2020.108579

358. Yoo SA A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis J. Exp. Med. 2012 209 871 886 10.1084/jem.20111783 22430489 PMC3328363 Yoo, S. A. et al. A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis. J. Exp. Med. 209 , 871–886 (2012). 22430489 10.1084/jem.20111783 PMC3328363

359. Olek MJ Multiple Sclerosis Ann. Intern. Med. 2021 174 ITC81 ITC96 10.7326/AITC202106150 34097429 Olek, M. J. Multiple Sclerosis. Ann. Intern. Med. 174 , ITC81–ITC96 (2021). 34097429 10.7326/AITC202106150

360. Way SW Popko B Harnessing the integrated stress response for the treatment of multiple sclerosis Lancet Neurol. 2016 15 434 443 10.1016/S1474-4422(15)00381-6 26873788 PMC4792730 Way, S. W. & Popko, B. Harnessing the integrated stress response for the treatment of multiple sclerosis. Lancet Neurol. 15 , 434–443 (2016). 26873788 10.1016/S1474-4422(15)00381-6 PMC4792730

361. Lin W Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress Brain 2006 129 1306 1318 10.1093/brain/awl044 16504972 Lin, W. et al. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain 129 , 1306–1318 (2006). 16504972 10.1093/brain/awl044

362. Huang H Neuroprotection by eIF2alpha-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss Cell Death Dis. 2017 8 e2936 10.1038/cddis.2017.329 28726788 PMC5550873 Huang, H. et al. Neuroprotection by eIF2alpha-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss. Cell Death Dis. 8 , e2936 (2017). 28726788 10.1038/cddis.2017.329 PMC5550873

363. Yousuf MS Endoplasmic reticulum stress in the dorsal root ganglia regulates large-conductance potassium channels and contributes to pain in a model of multiple sclerosis FASEB J. 2020 34 12577 12598 10.1096/fj.202001163R 32677089 Yousuf, M. S. et al. Endoplasmic reticulum stress in the dorsal root ganglia regulates large-conductance potassium channels and contributes to pain in a model of multiple sclerosis. FASEB J. 34 , 12577–12598 (2020). 32677089 10.1096/fj.202001163R

364. Inceoglu B Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain Proc. Natl. Acad. Sci. USA 2015 112 9082 9087 10.1073/pnas.1510137112 26150506 PMC4517273 Inceoglu, B. et al. Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proc. Natl. Acad. Sci. USA 112 , 9082–9087 (2015). 26150506 10.1073/pnas.1510137112 PMC4517273

365. Bisgaard TH Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment Nat. Rev. Gastroenterol. Hepatol. 2022 19 717 726 10.1038/s41575-022-00634-6 35732730 Bisgaard, T. H. et al. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nat. Rev. Gastroenterol. Hepatol. 19 , 717–726 (2022). 35732730 10.1038/s41575-022-00634-6

366. Danne C Skerniskyte J Marteyn B Sokol H Neutrophils: from IBD to the gut microbiota Nat. Rev. Gastroenterol. Hepatol. 2024 21 184 197 10.1038/s41575-023-00871-3 38110547 Danne, C., Skerniskyte, J., Marteyn, B. & Sokol, H. Neutrophils: from IBD to the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 21 , 184–197 (2024). 38110547 10.1038/s41575-023-00871-3

367. Shkoda A Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation Gastroenterology 2007 132 190 207 10.1053/j.gastro.2006.10.030 17241871 Shkoda, A. et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 132 , 190–207 (2007). 17241871 10.1053/j.gastro.2006.10.030

368. Cao, S. et al. The IRE1alpha/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease. J. Clin. Invest . 134 , e174198 (2024). 10.1172/JCI174198 PMC11214543 38722686

369. Ke X Gut bacterial metabolites modulate endoplasmic reticulum stress Genome Biol. 2021 22 292 10.1186/s13059-021-02496-8 34654459 PMC8518294 Ke, X. et al. Gut bacterial metabolites modulate endoplasmic reticulum stress. Genome Biol. 22 , 292 (2021). 34654459 10.1186/s13059-021-02496-8 PMC8518294

370. Ranjan, K. et al. Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response. J. Clin. Invest . 131 , e145472 (2021). 10.1172/JCI145472 PMC8409591 34623328

371. Larabi A Barnich N Nguyen HTT New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD Autophagy 2020 16 38 51 10.1080/15548627.2019.1635384 31286804 PMC6984609 Larabi, A., Barnich, N. & Nguyen, H. T. T. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy 16 , 38–51 (2020). 31286804 10.1080/15548627.2019.1635384 PMC6984609

372. Rees WD Enteroids derived from inflammatory bowel disease patients display dysregulated endoplasmic reticulum stress pathways, leading to differential inflammatory responses and dendritic cell maturation J. Crohns Colitis 2020 14 948 961 10.1093/ecco-jcc/jjz194 31796949 Rees, W. D. et al. Enteroids derived from inflammatory bowel disease patients display dysregulated endoplasmic reticulum stress pathways, leading to differential inflammatory responses and dendritic cell maturation. J. Crohns Colitis 14 , 948–961 (2020). 31796949 10.1093/ecco-jcc/jjz194

373. Al-Shaibi AA Human AGR2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel disease Cell Mol. Gastroenterol. Hepatol. 2021 12 1809 1830 10.1016/j.jcmgh.2021.07.001 34237462 PMC8551217 Al-Shaibi, A. A. et al. Human AGR2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel disease. Cell Mol. Gastroenterol. Hepatol. 12 , 1809–1830 (2021). 34237462 10.1016/j.jcmgh.2021.07.001 PMC8551217

374. Lee AS GRP78 induction in cancer: therapeutic and prognostic implications Cancer Res. 2007 67 3496 3499 10.1158/0008-5472.CAN-07-0325 17440054 Lee, A. S. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 67 , 3496–3499 (2007). 17440054 10.1158/0008-5472.CAN-07-0325

375. Duan X Molecular chaperone GRP94/GP96 in cancers: oncogenesis and therapeutic target Front. Oncol. 2021 11 629846 10.3389/fonc.2021.629846 33898309 PMC8062746 Duan, X. et al. Molecular chaperone GRP94/GP96 in cancers: oncogenesis and therapeutic target. Front. Oncol. 11 , 629846 (2021). 33898309 10.3389/fonc.2021.629846 PMC8062746

376. Kielbik, M., Szulc-Kielbik, I. & Klink, M. Calreticulin-multifunctional chaperone in immunogenic cell death: potential significance as a prognostic biomarker in ovarian cancer patients. Cells . 10 , 130 (2021). 10.3390/cells10010130 PMC7827772 33440842

377. van Schadewijk A van’t Wout EF Stolk J Hiemstra PS A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress Cell Stress Chaperones 2012 17 275 279 10.1007/s12192-011-0306-2 22038282 PMC3273559 van Schadewijk, A., van’t Wout, E. F., Stolk, J. & Hiemstra, P. S. A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress. Cell Stress Chaperones 17 , 275–279 (2012). 22038282 10.1007/s12192-011-0306-2 PMC3273559

378. Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med . 10 , eaar2036 (2018). 10.1126/scitranslmed.aar2036 PMC6045425 29720449

379. de la Cadena SG Hernandez-Fonseca K Camacho-Arroyo I Massieu L Glucose deprivation induces reticulum stress by the PERK pathway and caspase-7- and calpain-mediated caspase-12 activation Apoptosis 2014 19 414 427 10.1007/s10495-013-0930-7 24185830 de la Cadena, S. G., Hernandez-Fonseca, K., Camacho-Arroyo, I. & Massieu, L. Glucose deprivation induces reticulum stress by the PERK pathway and caspase-7- and calpain-mediated caspase-12 activation. Apoptosis 19 , 414–427 (2014). 24185830 10.1007/s10495-013-0930-7

380. Dorweiler B Activation of the proapoptotic unfolded protein response in plaques of the human carotid artery Eur. J. Vasc. Endovasc. Surg. 2014 48 248 257 10.1016/j.ejvs.2014.06.038 25060744 Dorweiler, B. et al. Activation of the proapoptotic unfolded protein response in plaques of the human carotid artery. Eur. J. Vasc. Endovasc. Surg. 48 , 248–257 (2014). 25060744 10.1016/j.ejvs.2014.06.038

381. Sabnis AJ Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma Proc. Natl. Acad. Sci. USA 2016 113 9015 9020 10.1073/pnas.1603883113 27450084 PMC4987817 Sabnis, A. J. et al. Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma. Proc. Natl. Acad. Sci. USA 113 , 9015–9020 (2016). 27450084 10.1073/pnas.1603883113 PMC4987817

382. Nourbakhsh M Circulating TRB3 and GRP78 levels in type 2 diabetes patients: crosstalk between glucose homeostasis and endoplasmic reticulum stress J. Endocrinol. Invest. 2022 45 649 655 10.1007/s40618-021-01683-5 34591271 Nourbakhsh, M. et al. Circulating TRB3 and GRP78 levels in type 2 diabetes patients: crosstalk between glucose homeostasis and endoplasmic reticulum stress. J. Endocrinol. Invest. 45 , 649–655 (2022). 34591271 10.1007/s40618-021-01683-5

383. Lim SO Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules World J. Gastroenterol. 2005 11 2072 2079 10.3748/wjg.v11.i14.2072 15810071 PMC4305774 Lim, S. O. et al. Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules. World J. Gastroenterol. 11 , 2072–2079 (2005). 15810071 10.3748/wjg.v11.i14.2072 PMC4305774

384. Bagratuni T XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments Blood 2010 116 250 253 10.1182/blood-2010-01-263236 20421453 Bagratuni, T. et al. XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments. Blood 116 , 250–253 (2010). 20421453 10.1182/blood-2010-01-263236

385. Leung-Hagesteijn C Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma Cancer Cell 2013 24 289 304 10.1016/j.ccr.2013.08.009 24029229 PMC4118579 Leung-Hagesteijn, C. et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 24 , 289–304 (2013). 24029229 10.1016/j.ccr.2013.08.009 PMC4118579

386. Jagannathan S Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib Leukemia 2015 29 2184 2191 10.1038/leu.2015.157 26108695 PMC4635337 Jagannathan, S. et al. Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia 29 , 2184–2191 (2015). 26108695 10.1038/leu.2015.157 PMC4635337

387. Moriya S Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells Int. J. Oncol. 2013 42 1541 1550 10.3892/ijo.2013.1870 23546223 PMC3661227 Moriya, S. et al. Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells. Int. J. Oncol. 42 , 1541–1550 (2013). 23546223 10.3892/ijo.2013.1870 PMC3661227

388. Raymundo DP Pharmacological targeting of IRE1 in cancer Trends Cancer 2020 6 1018 1030 10.1016/j.trecan.2020.07.006 32861679 Raymundo, D. P. et al. Pharmacological targeting of IRE1 in cancer. Trends Cancer 6 , 1018–1030 (2020). 32861679 10.1016/j.trecan.2020.07.006

389. Byrd JC Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia N. Engl. J. Med. 2013 369 32 42 10.1056/NEJMoa1215637 23782158 PMC3772525 Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369 , 32–42 (2013). 23782158 10.1056/NEJMoa1215637 PMC3772525

390. Xie H IRE1alpha RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers J. Clin. Invest. 2018 128 1300 1316 10.1172/JCI95864 29381485 PMC5873889 Xie, H. et al. IRE1alpha RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J. Clin. Invest. 128 , 1300–1316 (2018). 29381485 10.1172/JCI95864 PMC5873889

391. Sanches M Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors Nat. Commun. 2014 5 4202 10.1038/ncomms5202 25164867 PMC4486471 Sanches, M. et al. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat. Commun. 5 , 4202 (2014). 25164867 10.1038/ncomms5202 PMC4486471

392. Vieri M Targeting of BCR-ABL1 and IRE1alpha induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia Carcinogenesis 2021 42 272 284 10.1093/carcin/bgaa095 32915195 Vieri, M. et al. Targeting of BCR-ABL1 and IRE1alpha induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia. Carcinogenesis 42 , 272–284 (2021). 32915195 10.1093/carcin/bgaa095

393. Xiao R Inhibiting the IRE1alpha axis of the unfolded protein response enhances the antitumor effect of AZD1775 in TP53 mutant ovarian cancer Adv. Sci. 2022 9 e2105469 10.1002/advs.202105469 PMC9313493 35619328 Xiao, R. et al. Inhibiting the IRE1alpha axis of the unfolded protein response enhances the antitumor effect of AZD1775 in TP53 mutant ovarian cancer. Adv. Sci. 9 , e2105469 (2022). 10.1002/advs.202105469 PMC9313493 35619328

394. Harnoss JM Disruption of IRE1alpha through its kinase domain attenuates multiple myeloma Proc. Natl. Acad. Sci. USA 2019 116 16420 16429 10.1073/pnas.1906999116 31371506 PMC6697881 Harnoss, J. M. et al. Disruption of IRE1alpha through its kinase domain attenuates multiple myeloma. Proc. Natl. Acad. Sci. USA 116 , 16420–16429 (2019). 31371506 10.1073/pnas.1906999116 PMC6697881

395. Yamashita, Y. et al. Targeting adaptive IRE1alpha signaling and PLK2 in multiple myeloma: possible anti-tumor mechanisms of KIRA8 and nilotinib. Int. J. Mol. Sci . 21 , 6314 (2020). 10.3390/ijms21176314 PMC7504392 32878237

396. Gallagher, C. M. et al. Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6alpha branch. eLife . 5 , e11878 (2016). 10.7554/eLife.11878 PMC4954757 27435960

397. Gallagher, C. M. & Walter, P. Ceapins inhibit ATF6alpha signaling by selectively preventing transport of ATF6alpha to the Golgi apparatus during ER stress. eLife . 5 , e11880 (2016). 10.7554/eLife.11880 PMC4954756 27435962

398. Torres, S. E. et al. Ceapins block the unfolded protein response sensor ATF6alpha by inducing a neomorphic inter-organelle tether. eLife . 8 , e46595 (2019). 10.7554/eLife.46595 PMC6588346 31149896

399. Wang Z CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma J. Exp. Clin. Cancer Res. 2019 38 44 10.1186/s13046-019-1047-9 30704503 PMC6357486 Wang, Z. et al. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. J. Exp. Clin. Cancer Res. 38 , 44 (2019). 30704503 10.1186/s13046-019-1047-9 PMC6357486

400. Hurst KE Endoplasmic reticulum stress contributes to mitochondrial exhaustion of CD8(+) T cells Cancer Immunol. Res. 2019 7 476 486 10.1158/2326-6066.CIR-18-0182 30659052 PMC6397687 Hurst, K. E. et al. Endoplasmic reticulum stress contributes to mitochondrial exhaustion of CD8(+) T cells. Cancer Immunol. Res. 7 , 476–486 (2019). 30659052 10.1158/2326-6066.CIR-18-0182 PMC6397687

401. Szebenyi K Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology Nat. Neurosci. 2021 24 1542 1554 10.1038/s41593-021-00923-4 34675437 PMC8553627 Szebenyi, K. et al. Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Nat. Neurosci. 24 , 1542–1554 (2021). 34675437 10.1038/s41593-021-00923-4 PMC8553627

402. Yodsanit N Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms Bioact. Mater. 2023 26 52 63 36875050 10.1016/j.bioactmat.2023.02.009 PMC9975632 Yodsanit, N. et al. Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms. Bioact. Mater. 26 , 52–63 (2023). 36875050 10.1016/j.bioactmat.2023.02.009 PMC9975632

403. Smith AL Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK) J. Med. Chem. 2015 58 1426 1441 10.1021/jm5017494 25587754 Smith, A. L. et al. Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 58 , 1426–1441 (2015). 25587754 10.1021/jm5017494

404. Tameire F ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression Nat. Cell Biol. 2019 21 889 899 10.1038/s41556-019-0347-9 31263264 PMC6608727 Tameire, F. et al. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat. Cell Biol. 21 , 889–899 (2019). 31263264 10.1038/s41556-019-0347-9 PMC6608727

405. Rabouw HH Small molecule ISRIB suppresses the integrated stress response within a defined window of activation Proc. Natl. Acad. Sci. USA 2019 116 2097 2102 10.1073/pnas.1815767116 30674674 PMC6369741 Rabouw, H. H. et al. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc. Natl. Acad. Sci. USA 116 , 2097–2102 (2019). 30674674 10.1073/pnas.1815767116 PMC6369741

406. Wang X CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR J. Hematol. Oncol. 2022 15 122 10.1186/s13045-022-01345-w 36038948 PMC9425971 Wang, X. et al. CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR. J. Hematol. Oncol. 15 , 122 (2022). 36038948 10.1186/s13045-022-01345-w PMC9425971

407. Li Z BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2alpha phosphorylation Gastroenterology 2022 162 1256 1271.e1214 10.1053/j.gastro.2021.12.249 34951995 PMC9436032 Li, Z. et al. BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2alpha phosphorylation. Gastroenterology 162 , 1256–1271.e1214 (2022). 34951995 10.1053/j.gastro.2021.12.249 PMC9436032

408. Ghaddar N The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer Nat. Commun. 2021 12 4651 10.1038/s41467-021-24661-0 34330898 PMC8324901 Ghaddar, N. et al. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Nat. Commun. 12 , 4651 (2021). 34330898 10.1038/s41467-021-24661-0 PMC8324901

409. Schoenhacker-Alte B Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis Cancer Lett. 2017 404 79 88 10.1016/j.canlet.2017.07.009 28716523 Schoenhacker-Alte, B. et al. Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis. Cancer Lett. 404 , 79–88 (2017). 28716523 10.1016/j.canlet.2017.07.009

410. Heffeter P The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo Eur. J. Cancer 2013 49 3366 3375 10.1016/j.ejca.2013.05.018 23790465 PMC3807657 Heffeter, P. et al. The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo. Eur. J. Cancer 49 , 3366–3375 (2013). 23790465 10.1016/j.ejca.2013.05.018 PMC3807657

411. Wernitznig D First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro Metallomics 2019 11 1044 1048 10.1039/c9mt00051h 30942231 Wernitznig, D. et al. First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro. Metallomics 11 , 1044–1048 (2019). 30942231 10.1039/c9mt00051h

412. Cerezo M Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance Cancer Cell 2016 29 805 819 10.1016/j.ccell.2016.04.013 27238082 Cerezo, M. et al. Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Cancer Cell 29 , 805–819 (2016). 27238082 10.1016/j.ccell.2016.04.013

413. Zheng S iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers Cell Death Differ. 2023 30 327 340 10.1038/s41418-022-01086-w 36380064 PMC9950372 Zheng, S. et al. iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers. Cell Death Differ. 30 , 327–340 (2023). 36380064 10.1038/s41418-022-01086-w PMC9950372

414. Ha DP Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations Neoplasia 2022 33 100837 10.1016/j.neo.2022.100837 36162331 PMC9516447 Ha, D. P. et al. Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations. Neoplasia 33 , 100837 (2022). 36162331 10.1016/j.neo.2022.100837 PMC9516447

415. Lee HY GRP78 protein expression as prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer Cancer Res. Treat. 2015 47 804 812 10.4143/crt.2014.121 25687871 PMC4614215 Lee, H. Y. et al. GRP78 protein expression as prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer. Cancer Res. Treat. 47 , 804–812 (2015). 25687871 10.4143/crt.2014.121 PMC4614215

416. Hong Z Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy Cancer Res. 2022 82 1298 1312 10.1158/0008-5472.CAN-21-2229 35045984 PMC8983553 Hong, Z. et al. Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy. Cancer Res. 82 , 1298–1312 (2022). 35045984 10.1158/0008-5472.CAN-21-2229 PMC8983553

417. Guo XB Effects of gene polymorphisms in the endoplasmic reticulum stress pathway on clinical outcomes of chemoradiotherapy in Chinese patients with nasopharyngeal carcinoma Acta Pharmacol. Sin. 2017 38 571 580 10.1038/aps.2016.148 28216622 PMC5386314 Guo, X. B. et al. Effects of gene polymorphisms in the endoplasmic reticulum stress pathway on clinical outcomes of chemoradiotherapy in Chinese patients with nasopharyngeal carcinoma. Acta Pharmacol. Sin. 38 , 571–580 (2017). 28216622 10.1038/aps.2016.148 PMC5386314

418. Kalbasi A Ribas A Tumour-intrinsic resistance to immune checkpoint blockade Nat. Rev. Immunol. 2020 20 25 39 10.1038/s41577-019-0218-4 31570880 PMC8499690 Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20 , 25–39 (2020). 31570880 10.1038/s41577-019-0218-4 PMC8499690

419. Iglesias-Escudero M Arias-Gonzalez N Martinez-Caceres E Regulatory cells and the effect of cancer immunotherapy Mol. Cancer 2023 22 26 10.1186/s12943-023-01714-0 36739406 PMC9898962 Iglesias-Escudero, M., Arias-Gonzalez, N. & Martinez-Caceres, E. Regulatory cells and the effect of cancer immunotherapy. Mol. Cancer 22 , 26 (2023). 36739406 10.1186/s12943-023-01714-0 PMC9898962

420. Tison A Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases Nat. Rev. Rheumatol. 2022 18 641 656 10.1038/s41584-022-00841-0 36198831 Tison, A. et al. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat. Rev. Rheumatol. 18 , 641–656 (2022). 36198831 10.1038/s41584-022-00841-0

421. Dong H Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion Nat. Med. 2002 8 793 800 10.1038/nm730 12091876 Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8 , 793–800 (2002). 12091876 10.1038/nm730

422. Liu J Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages Hepatology 2019 70 241 258 10.1002/hep.30607 30854665 PMC6597282 Liu, J. et al. Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology 70 , 241–258 (2019). 30854665 10.1002/hep.30607 PMC6597282

423. Li, C. et al. THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy. J. Immunother. Cancer 9 , e002443 (2021). 10.1136/jitc-2021-002443 PMC8330570 34341130

424. Cha JH Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1 Mol. Cell 2018 71 606 620.e607 10.1016/j.molcel.2018.07.030 30118680 PMC6786495 Cha, J. H. et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol. Cell 71 , 606–620.e607 (2018). 30118680 10.1016/j.molcel.2018.07.030 PMC6786495

425. Xiang Y Redirecting chemotherapeutics to the endoplasmic reticulum increases tumor immunogenicity and potentiates anti-PD-L1 therapy Small 2022 18 e2104591 10.1002/smll.202104591 34859582 Xiang, Y. et al. Redirecting chemotherapeutics to the endoplasmic reticulum increases tumor immunogenicity and potentiates anti-PD-L1 therapy. Small 18 , e2104591 (2022). 34859582 10.1002/smll.202104591

426. Guttman, O. et al. Antigen-derived peptides engage the ER stress sensor IRE1alpha to curb dendritic cell cross-presentation. J. Cell Biol . 221 , e202111068 (2022). 10.1083/jcb.202111068 PMC9036094 35446348

427. Jiang M Dual Inhibition of endoplasmic reticulum stress and oxidation stress manipulates the polarization of macrophages under hypoxia to sensitize immunotherapy ACS Nano 2021 15 14522 14534 10.1021/acsnano.1c04068 34414762 Jiang, M. et al. Dual Inhibition of endoplasmic reticulum stress and oxidation stress manipulates the polarization of macrophages under hypoxia to sensitize immunotherapy. ACS Nano 15 , 14522–14534 (2021). 34414762 10.1021/acsnano.1c04068

428. Lin J Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer Nat. Commun. 2021 12 5321 10.1038/s41467-021-25684-3 34493732 PMC8423755 Lin, J. et al. Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer. Nat. Commun. 12 , 5321 (2021). 34493732 10.1038/s41467-021-25684-3 PMC8423755

429. Yang Q Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy Theranostics 2020 10 8382 8399 10.7150/thno.45391 32724476 PMC7381738 Yang, Q. et al. Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy. Theranostics 10 , 8382–8399 (2020). 32724476 10.7150/thno.45391 PMC7381738

430. Katoh, Y. et al. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating beta-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J. Immunother. Cancer 10 , e004616 (2022). 10.1136/jitc-2022-004616 PMC9260842 35793868

431. Huang X Rationally designed heptamethine cyanine photosensitizers that amplify tumor-specific endoplasmic reticulum stress and boost antitumor immunity Small 2022 18 e2202728 10.1002/smll.202202728 35796192 Huang, X. et al. Rationally designed heptamethine cyanine photosensitizers that amplify tumor-specific endoplasmic reticulum stress and boost antitumor immunity. Small 18 , e2202728 (2022). 35796192 10.1002/smll.202202728

432. Rufo N Garg AD Agostinis P The unfolded protein response in immunogenic cell death and cancer immunotherapy Trends Cancer 2017 3 643 658 10.1016/j.trecan.2017.07.002 28867168 Rufo, N., Garg, A. D. & Agostinis, P. The unfolded protein response in immunogenic cell death and cancer immunotherapy. Trends Cancer 3 , 643–658 (2017). 28867168 10.1016/j.trecan.2017.07.002

433. Mandula JK Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses Cancer Cell 2022 40 1145 1160.e1149 10.1016/j.ccell.2022.08.016 36150390 PMC9561067 Mandula, J. K. et al. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses. Cancer Cell 40 , 1145–1160.e1149 (2022). 36150390 10.1016/j.ccell.2022.08.016 PMC9561067

434. Gumber D Wang LD Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion EBioMedicine 2022 77 103941 10.1016/j.ebiom.2022.103941 35301179 PMC8927848 Gumber, D. & Wang, L. D. Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion. EBioMedicine 77 , 103941 (2022). 35301179 10.1016/j.ebiom.2022.103941 PMC8927848

435. Ibanez J GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells Cell Rep. Med. 2023 4 101297 10.1016/j.xcrm.2023.101297 37992682 PMC10694756 Ibanez, J. et al. GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells. Cell Rep. Med. 4 , 101297 (2023). 37992682 10.1016/j.xcrm.2023.101297 PMC10694756

436. Wang, S. et al. Cell-surface GRP78-targeted chimeric antigen receptor T cells eliminate lung cancer tumor xenografts. Int. J. Mol. Sci . 25 , 564 (2024). 10.3390/ijms25010564 PMC10779323 38203736

437. Pan X Inhibition of chemically and mechanically activated Piezo1 channels as a mechanism for ameliorating atherosclerosis with salvianolic acid B Br. J. Pharmacol. 2022 179 3778 3814 10.1111/bph.15826 35194776 Pan, X. et al. Inhibition of chemically and mechanically activated Piezo1 channels as a mechanism for ameliorating atherosclerosis with salvianolic acid B. Br. J. Pharmacol. 179 , 3778–3814 (2022). 35194776 10.1111/bph.15826

438. Chen R Salvianolic acid B protects against doxorubicin induced cardiac dysfunction via inhibition of ER stress mediated cardiomyocyte apoptosis Toxicol. Res. 2016 5 1335 1345 10.1039/C6TX00111D PMC6062089 30090438 Chen, R. et al. Salvianolic acid B protects against doxorubicin induced cardiac dysfunction via inhibition of ER stress mediated cardiomyocyte apoptosis. Toxicol. Res. 5 , 1335–1345 (2016). 10.1039/c6tx00111d PMC6062089 30090438

439. Chen RC Salvianolic acid B attenuates doxorubicin-induced ER stress by inhibiting TRPC3 and TRPC6 mediated Ca(2+) overload in rat cardiomyocytes Toxicol. Lett. 2017 276 21 30 10.1016/j.toxlet.2017.04.010 28495616 Chen, R. C. et al. Salvianolic acid B attenuates doxorubicin-induced ER stress by inhibiting TRPC3 and TRPC6 mediated Ca(2+) overload in rat cardiomyocytes. Toxicol. Lett. 276 , 21–30 (2017). 28495616 10.1016/j.toxlet.2017.04.010

440. Chen JC Wu ML Huang KC Lin WW HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression Cardiovasc Res. 2008 80 138 150 10.1093/cvr/cvn160 18556704 Chen, J. C., Wu, M. L., Huang, K. C. & Lin, W. W. HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression. Cardiovasc Res. 80 , 138–150 (2008). 18556704 10.1093/cvr/cvn160

441. Yang PM Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies Cancer Res. 2010 70 7699 7709 10.1158/0008-5472.CAN-10-1626 20876807 Yang, P. M. et al. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 70 , 7699–7709 (2010). 20876807 10.1158/0008-5472.CAN-10-1626

442. Li F Chang Z Li Y Sun J In vivo and in vitro impact of atorvastatin against myocardial ischaemia-reperfusion injury by upregulation of silent information regulator l and attenuation of endoplasmic reticulum stress-induced apoptosis J. Drug Target. 2022 30 1076 1087 35722944 10.1080/1061186X.2022.2091577 Li, F., Chang, Z., Li, Y. & Sun, J. In vivo and in vitro impact of atorvastatin against myocardial ischaemia-reperfusion injury by upregulation of silent information regulator l and attenuation of endoplasmic reticulum stress-induced apoptosis. J. Drug Target. 30 , 1076–1087 (2022). 35722944 10.1080/1061186X.2022.2091577

443. Chen Q Metformin attenuates ER stress-induced mitochondrial dysfunction Transl. Res. 2017 190 40 50 10.1016/j.trsl.2017.09.003 29040818 PMC5705457 Chen, Q. et al. Metformin attenuates ER stress-induced mitochondrial dysfunction. Transl. Res. 190 , 40–50 (2017). 29040818 10.1016/j.trsl.2017.09.003 PMC5705457

444. Wang S Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1alpha/X box-binding protein-1 pathway Br. J. Pharmacol. 2016 173 2402 2418 10.1111/bph.13516 27186946 PMC4945765 Wang, S. et al. Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1alpha/X box-binding protein-1 pathway. Br. J. Pharmacol. 173 , 2402–2418 (2016). 27186946 10.1111/bph.13516 PMC4945765

445. Xu X Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease Cell Stem Cell 2022 29 840 855.e847 10.1016/j.stem.2022.03.003 35395180 PMC9302582 Xu, X. et al. Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease. Cell Stem Cell 29 , 840–855.e847 (2022). 35395180 10.1016/j.stem.2022.03.003 PMC9302582

446. George I beta-adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines Cardiovasc Res. 2011 91 447 455 10.1093/cvr/cvr106 21493701 George, I. et al. beta-adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines. Cardiovasc Res. 91 , 447–455 (2011). 21493701 10.1093/cvr/cvr106

447. Liu Y Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways Can. J. Cardiol. 2014 30 368 375 24565258 10.1016/j.cjca.2013.11.001 Liu, Y. et al. Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways. Can. J. Cardiol. 30 , 368–375 (2014). 24565258 10.1016/j.cjca.2013.11.001

448. Gong W Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure Br. J. Pharmacol. 2013 170 1396 1409 10.1111/bph.12346 24032459 PMC3838686 Gong, W. et al. Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure. Br. J. Pharmacol. 170 , 1396–1409 (2013). 24032459 10.1111/bph.12346 PMC3838686

449. Shakeri A Curcumin and its analogues protect from endoplasmic reticulum stress: mechanisms and pathways Pharm. Res. 2019 146 104335 10.1016/j.phrs.2019.104335 31265891 Shakeri, A. et al. Curcumin and its analogues protect from endoplasmic reticulum stress: mechanisms and pathways. Pharm. Res. 146 , 104335 (2019). 10.1016/j.phrs.2019.104335 31265891

450. Li J Relief of oxidative stress and cardiomyocyte apoptosis by using curcumin nanoparticles Colloids Surf. B Biointerfaces 2017 153 174 182 10.1016/j.colsurfb.2017.02.023 28237821 Li, J. et al. Relief of oxidative stress and cardiomyocyte apoptosis by using curcumin nanoparticles. Colloids Surf. B Biointerfaces 153 , 174–182 (2017). 28237821 10.1016/j.colsurfb.2017.02.023

451. Li FJ Inhibition of ER stress using tauroursodeoxycholic acid rescues obesity-evoked cardiac remodeling and contractile anomalies through regulation of ferroptosis Chem. Biol. Interact. 2024 398 111104 10.1016/j.cbi.2024.111104 38906502 Li, F. J. et al. Inhibition of ER stress using tauroursodeoxycholic acid rescues obesity-evoked cardiac remodeling and contractile anomalies through regulation of ferroptosis. Chem. Biol. Interact. 398 , 111104 (2024). 38906502 10.1016/j.cbi.2024.111104

452. Zha X Yue Y Dong N Xiong S Endoplasmic reticulum stress aggravates viral myocarditis by raising inflammation through the IRE1-associated NF-kappaB pathway Can. J. Cardiol. 2015 31 1032 1040 26111668 10.1016/j.cjca.2015.03.003 Zha, X., Yue, Y., Dong, N. & Xiong, S. Endoplasmic reticulum stress aggravates viral myocarditis by raising inflammation through the IRE1-associated NF-kappaB pathway. Can. J. Cardiol. 31 , 1032–1040 (2015). 26111668 10.1016/j.cjca.2015.03.003

453. Moellmann J The sodium-glucose co-transporter-2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR signalling, endoplasmic reticulum stress and apoptosis Diabetes Obes. Metab. 2022 24 2263 2272 10.1111/dom.14814 35801343 Moellmann, J. et al. The sodium-glucose co-transporter-2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR signalling, endoplasmic reticulum stress and apoptosis. Diabetes Obes. Metab. 24 , 2263–2272 (2022). 35801343 10.1111/dom.14814

454. Shih JY Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench Diabetes 2021 70 262 267 10.2337/db20-0840 33115828 Shih, J. Y. et al. Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench. Diabetes 70 , 262–267 (2021). 33115828 10.2337/db20-0840

455. Duan Q Song P Ding Y Zou MH Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo Br. J. Pharmacol. 2017 174 2140 2151 10.1111/bph.13833 28436023 PMC5466537 Duan, Q., Song, P., Ding, Y. & Zou, M. H. Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br. J. Pharmacol. 174 , 2140–2151 (2017). 28436023 10.1111/bph.13833 PMC5466537

456. Goswami P Downregulation of ATF-4 attenuates the endoplasmic reticulum stress-mediated neuroinflammation and cognitive impairment in experimentally induced Alzheimer’s disease model Mol. Neurobiol. 2024 61 5071 5082 10.1007/s12035-023-03861-3 38159199 Goswami, P. et al. Downregulation of ATF-4 attenuates the endoplasmic reticulum stress-mediated neuroinflammation and cognitive impairment in experimentally induced Alzheimer’s disease model. Mol. Neurobiol. 61 , 5071–5082 (2024). 38159199 10.1007/s12035-023-03861-3

457. Lin CH Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARgamma dependent signaling Exp. Cell Res. 2018 370 312 321 10.1016/j.yexcr.2018.06.033 29964054 Lin, C. H. et al. Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARgamma dependent signaling. Exp. Cell Res. 370 , 312–321 (2018). 29964054 10.1016/j.yexcr.2018.06.033

458. Gupta P Rivastigmine attenuates the Alzheimer’s disease related protein degradation and apoptotic neuronal death signalling Biochem. J. 2021 478 1435 1451 10.1042/BCJ20200754 33660768 Gupta, P. et al. Rivastigmine attenuates the Alzheimer’s disease related protein degradation and apoptotic neuronal death signalling. Biochem. J. 478 , 1435–1451 (2021). 33660768 10.1042/BCJ20200754

459. Motawi TK Al-Kady RH Senousy MA Abdelraouf SM Repaglinide elicits a neuroprotective effect in rotenone-induced Parkinson’s disease in rats: emphasis on targeting the DREAM-ER stress BiP/ATF6/CHOP trajectory and activation of mitophagy ACS Chem. Neurosci. 2023 14 180 194 10.1021/acschemneuro.2c00656 36538285 Motawi, T. K., Al-Kady, R. H., Senousy, M. A. & Abdelraouf, S. M. Repaglinide elicits a neuroprotective effect in rotenone-induced Parkinson’s disease in rats: emphasis on targeting the DREAM-ER stress BiP/ATF6/CHOP trajectory and activation of mitophagy. ACS Chem. Neurosci. 14 , 180–194 (2023). 36538285 10.1021/acschemneuro.2c00656

460. Celardo I Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease Cell Death Dis. 2016 7 e2271 10.1038/cddis.2016.173 27336715 PMC5143399 Celardo, I. et al. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease. Cell Death Dis. 7 , e2271 (2016). 27336715 10.1038/cddis.2016.173 PMC5143399

461. Chiang MC Rosiglitazone activation of PPARgamma-dependent signaling is neuroprotective in mutant huntingtin expressing cells Exp. Cell Res. 2015 338 183 193 10.1016/j.yexcr.2015.09.005 26362846 Chiang, M. C. et al. Rosiglitazone activation of PPARgamma-dependent signaling is neuroprotective in mutant huntingtin expressing cells. Exp. Cell Res. 338 , 183–193 (2015). 26362846 10.1016/j.yexcr.2015.09.005

462. Varadarajan S The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration Cell Death Differ. 2015 22 1388 1396 10.1038/cdd.2015.1 25656655 PMC4495362 Varadarajan, S. et al. The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration. Cell Death Differ. 22 , 1388–1396 (2015). 25656655 10.1038/cdd.2015.1 PMC4495362

463. Ochiai T Tauroursodeoxycholic acid attenuates diet-induced and age-related peripheral endoplasmic reticulum stress and cerebral amyloid pathology in a mouse model of Alzheimer’s disease J. Prev. Alzheimers Dis. 2021 8 483 494 10.14283/jpad.2021.33 34585224 PMC12280779 Ochiai, T. et al. Tauroursodeoxycholic acid attenuates diet-induced and age-related peripheral endoplasmic reticulum stress and cerebral amyloid pathology in a mouse model of Alzheimer’s disease. J. Prev. Alzheimers Dis. 8 , 483–494 (2021). 34585224 10.14283/jpad.2021.33 PMC12280779

464. Shi Y Salvianolic acid B improved insulin resistance through suppression of hepatic ER stress in ob/ob mice Biochem. Biophys. Res. Commun. 2020 526 733 737 10.1016/j.bbrc.2020.03.124 32265029 Shi, Y. et al. Salvianolic acid B improved insulin resistance through suppression of hepatic ER stress in ob/ob mice. Biochem. Biophys. Res. Commun. 526 , 733–737 (2020). 32265029 10.1016/j.bbrc.2020.03.124

465. Wang L Curcumin inhibits lipolysis via suppression of ER stress in adipose tissue and prevents hepatic insulin resistance J. Lipid Res. 2016 57 1243 1255 10.1194/jlr.M067397 27220352 PMC4918853 Wang, L. et al. Curcumin inhibits lipolysis via suppression of ER stress in adipose tissue and prevents hepatic insulin resistance. J. Lipid Res. 57 , 1243–1255 (2016). 27220352 10.1194/jlr.M067397 PMC4918853

466. Breton-Romero R Liraglutide treatment reduces endothelial endoplasmic reticulum stress and insulin resistance in patients with diabetes mellitus J. Am. Heart Assoc. 2018 7 e009379 10.1161/JAHA.118.009379 30371206 PMC6222937 Breton-Romero, R. et al. Liraglutide treatment reduces endothelial endoplasmic reticulum stress and insulin resistance in patients with diabetes mellitus. J. Am. Heart Assoc. 7 , e009379 (2018). 30371206 10.1161/JAHA.118.009379 PMC6222937

467. Shimoda M The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes Diabetologia 2011 54 1098 1108 10.1007/s00125-011-2069-9 21340625 PMC3071950 Shimoda, M. et al. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia 54 , 1098–1108 (2011). 21340625 10.1007/s00125-011-2069-9 PMC3071950

468. Lei L Alpha-lipoic acid attenuates endoplasmic reticulum stress-induced insulin resistance by improving mitochondrial function in HepG2 cells Cell Signal. 2016 28 1441 1450 10.1016/j.cellsig.2016.06.024 27377964 Lei, L. et al. Alpha-lipoic acid attenuates endoplasmic reticulum stress-induced insulin resistance by improving mitochondrial function in HepG2 cells. Cell Signal. 28 , 1441–1450 (2016). 27377964 10.1016/j.cellsig.2016.06.024

469. Nakatsuka A Yamaguchi S Wada J GRP78 contributes to the beneficial effects of SGLT2 inhibitor on proximal tubular cells in DKD Diabetes 2024 73 763 779 10.2337/db23-0581 38394641 Nakatsuka, A., Yamaguchi, S. & Wada, J. GRP78 contributes to the beneficial effects of SGLT2 inhibitor on proximal tubular cells in DKD. Diabetes 73 , 763–779 (2024). 38394641 10.2337/db23-0581

470. Zhang X Resveratrol protected acrolein-induced ferroptosis and insulin secretion dysfunction via ER-stress- related PERK pathway in MIN6 cells Toxicology 2022 465 153048 10.1016/j.tox.2021.153048 34813903 Zhang, X. et al. Resveratrol protected acrolein-induced ferroptosis and insulin secretion dysfunction via ER-stress- related PERK pathway in MIN6 cells. Toxicology 465 , 153048 (2022). 34813903 10.1016/j.tox.2021.153048

471. Lee ES Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model Nephrol. Dial. Transpl. 2016 31 391 400 10.1093/ndt/gfv377 26567248 Lee, E. S. et al. Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model. Nephrol. Dial. Transpl. 31 , 391–400 (2016). 10.1093/ndt/gfv377 26567248

472. Diaz-Morales N Does metformin modulate endoplasmic reticulum stress and autophagy in type 2 diabetic peripheral blood mononuclear cells? Antioxid. Redox Signal 2018 28 1562 1569 10.1089/ars.2017.7409 29061071 Diaz-Morales, N. et al. Does metformin modulate endoplasmic reticulum stress and autophagy in type 2 diabetic peripheral blood mononuclear cells?. Antioxid. Redox Signal 28 , 1562–1569 (2018). 29061071 10.1089/ars.2017.7409

473. Cheang WS Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5’ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway Arterioscler. Thromb. Vasc. Biol. 2014 34 830 836 10.1161/ATVBAHA.113.301938 24482374 Cheang, W. S. et al. Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5’ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway. Arterioscler. Thromb. Vasc. Biol. 34 , 830–836 (2014). 24482374 10.1161/ATVBAHA.113.301938

474. Cao Q Sitagliptin reduces endothelial dysfunction and apoptosis induced by high-fat diet and palmitate in thoracic aortas and endothelial cells via ROS-ER stress-CHOP pathway Front. Pharmacol. 2021 12 670389 10.3389/fphar.2021.670389 34531738 PMC8438525 Cao, Q. et al. Sitagliptin reduces endothelial dysfunction and apoptosis induced by high-fat diet and palmitate in thoracic aortas and endothelial cells via ROS-ER stress-CHOP pathway. Front. Pharmacol. 12 , 670389 (2021). 34531738 10.3389/fphar.2021.670389 PMC8438525

475. Swe MT Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats Clin. Sci. 2019 133 2415 2430 10.1042/CS20190863 31769484 Swe, M. T. et al. Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. Clin. Sci. 133 , 2415–2430 (2019). 10.1042/CS20190863 31769484

476. Zheng M Curcumin induces apoptotic cell death of activated human CD4+ T cells via increasing endoplasmic reticulum stress and mitochondrial dysfunction Int. Immunopharmacol. 2013 15 517 523 10.1016/j.intimp.2013.02.002 23415873 Zheng, M. et al. Curcumin induces apoptotic cell death of activated human CD4+ T cells via increasing endoplasmic reticulum stress and mitochondrial dysfunction. Int. Immunopharmacol. 15 , 517–523 (2013). 23415873 10.1016/j.intimp.2013.02.002

477. Chen C Exosomes derived from M2 microglial cells modulated by 1070-nm light improve cognition in an Alzheimer’s disease mouse model Adv. Sci. 2023 10 e2304025 10.1002/advs.202304025 PMC10646245 37702115 Chen, C. et al. Exosomes derived from M2 microglial cells modulated by 1070-nm light improve cognition in an Alzheimer’s disease mouse model. Adv. Sci. 10 , e2304025 (2023). 10.1002/advs.202304025 PMC10646245 37702115

478. Gao B Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis EMBO Rep. 2008 9 480 485 10.1038/embor.2008.37 18369366 PMC2373369 Gao, B. et al. Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep. 9 , 480–485 (2008). 18369366 10.1038/embor.2008.37 PMC2373369

479. Li X Inhibition of transient receptor potential melastatin 7 (TRPM7) channel induces RA FLSs apoptosis through endoplasmic reticulum (ER) stress Clin. Rheumatol. 2014 33 1565 1574 10.1007/s10067-014-2599-x 24733250 Li, X. et al. Inhibition of transient receptor potential melastatin 7 (TRPM7) channel induces RA FLSs apoptosis through endoplasmic reticulum (ER) stress. Clin. Rheumatol. 33 , 1565–1574 (2014). 24733250 10.1007/s10067-014-2599-x

480. Kars M Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women Diabetes 2010 59 1899 1905 10.2337/db10-0308 20522594 PMC2911053 Kars, M. et al. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59 , 1899–1905 (2010). 20522594 10.2337/db10-0308 PMC2911053

481. Inan S Wei H The cytoprotective effects of dantrolene: a ryanodine receptor antagonist Anesth. Analg. 2010 111 1400 1410 10.1213/ANE.0b013e3181f7181c 20861418 PMC9382853 Inan, S. & Wei, H. The cytoprotective effects of dantrolene: a ryanodine receptor antagonist. Anesth. Analg. 111 , 1400–1410 (2010). 20861418 10.1213/ANE.0b013e3181f7181c PMC9382853

482. Abreu, D. et al. A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome. JCI Insight 6 , e145188 (2021). 10.1172/jci.insight.145188 PMC8410026 34185708

483. Liiv M ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome Nat. Commun. 2024 15 6143 10.1038/s41467-024-50502-x 39034309 PMC11271478 Liiv, M. et al. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome. Nat. Commun. 15 , 6143 (2024). 39034309 10.1038/s41467-024-50502-x PMC11271478

484. Lin MJ Cancer vaccines: the next immunotherapy frontier Nat. Cancer 2022 3 911 926 10.1038/s43018-022-00418-6 35999309 Lin, M. J. et al. Cancer vaccines: the next immunotherapy frontier. Nat. Cancer 3 , 911–926 (2022). 35999309 10.1038/s43018-022-00418-6

485. Boozari B Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma Gut 2010 59 1416 1426 10.1136/gut.2009.196519 20675696 Boozari, B. et al. Antitumoural immunity by virus-mediated immunogenic apoptosis inhibits metastatic growth of hepatocellular carcinoma. Gut 59 , 1416–1426 (2010). 20675696 10.1136/gut.2009.196519

486. Zheng Y Photodynamic-therapy activates immune response by disrupting immunity homeostasis of tumor cells, which generates vaccine for cancer therapy Int. J. Biol. Sci. 2016 12 120 132 10.7150/ijbs.12852 26722223 PMC4679404 Zheng, Y. et al. Photodynamic-therapy activates immune response by disrupting immunity homeostasis of tumor cells, which generates vaccine for cancer therapy. Int. J. Biol. Sci. 12 , 120–132 (2016). 26722223 10.7150/ijbs.12852 PMC4679404

487. Zhang M A self-reporting fluorescent salicylaldehyde-chlorambucil conjugate as a type-II ICD inducer for cancer vaccines Adv. Mater. 2022 34 e2205701 10.1002/adma.202205701 35863361 Zhang, M. et al. A self-reporting fluorescent salicylaldehyde-chlorambucil conjugate as a type-II ICD inducer for cancer vaccines. Adv. Mater. 34 , e2205701 (2022). 35863361 10.1002/adma.202205701

488. Wan J Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination Proc. Natl. Acad. Sci. USA 2023 120 e2210385120 10.1073/pnas.2210385120 36787350 PMC9974508 Wan, J. et al. Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination. Proc. Natl. Acad. Sci. USA 120 , e2210385120 (2023). 36787350 10.1073/pnas.2210385120 PMC9974508

489. Wang G The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors J. Exp. Clin. Cancer Res. 2023 42 284 10.1186/s13046-023-02848-1 37891570 PMC10604416 Wang, G. et al. The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors. J. Exp. Clin. Cancer Res. 42 , 284 (2023). 37891570 10.1186/s13046-023-02848-1 PMC10604416

490. Han KH Immunogenic extracellular vesicles derived from endoplasmic reticulum-stressed tumor cells: implications as the therapeutic cancer vaccine ACS Nano 2024 18 199 209 10.1021/acsnano.3c05645 38109681 Han, K. H. et al. Immunogenic extracellular vesicles derived from endoplasmic reticulum-stressed tumor cells: implications as the therapeutic cancer vaccine. ACS Nano 18 , 199–209 (2024). 38109681 10.1021/acsnano.3c05645

491. Tian X Endoplasmic reticulum-targeting near-infrared fluorescent probe for CYP2J2 activity and its imaging application in endoplasmic reticulum stress and tumor Anal. Chem. 2022 94 9572 9577 10.1021/acs.analchem.2c00425 35770896 Tian, X. et al. Endoplasmic reticulum-targeting near-infrared fluorescent probe for CYP2J2 activity and its imaging application in endoplasmic reticulum stress and tumor. Anal. Chem. 94 , 9572–9577 (2022). 35770896 10.1021/acs.analchem.2c00425

492. Fujisawa A Chemical profiling of the endoplasmic reticulum proteome using designer labeling reagents J. Am. Chem. Soc. 2018 140 17060 17070 10.1021/jacs.8b08606 30433779 Fujisawa, A. et al. Chemical profiling of the endoplasmic reticulum proteome using designer labeling reagents. J. Am. Chem. Soc. 140 , 17060–17070 (2018). 30433779 10.1021/jacs.8b08606

493. Wang, Y. et al. An NIR-fluorophore-based therapeutic endoplasmic reticulum stress inducer. Adv. Mater. , e1800475. 10.1002/adma.201800475 (2018). 10.1002/adma.201800475 29961960

494. Chen X A photoactivatable theranostic probe for simultaneous oxidative stress-triggered multi-color cellular imaging and photodynamic therapy Biomaterials 2022 287 121680 10.1016/j.biomaterials.2022.121680 35872556 Chen, X. et al. A photoactivatable theranostic probe for simultaneous oxidative stress-triggered multi-color cellular imaging and photodynamic therapy. Biomaterials 287 , 121680 (2022). 35872556 10.1016/j.biomaterials.2022.121680

495. Man H Hybrid labeling system for dSTORM imaging of endoplasmic reticulum for uncovering ultrastructural transformations under stress conditions Biosens. Bioelectron. 2021 189 113378 10.1016/j.bios.2021.113378 34087723 Man, H. et al. Hybrid labeling system for dSTORM imaging of endoplasmic reticulum for uncovering ultrastructural transformations under stress conditions. Biosens. Bioelectron. 189 , 113378 (2021). 34087723 10.1016/j.bios.2021.113378

496. Pavan Grandhi TS Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation Biomaterials 2017 142 171 185 10.1016/j.biomaterials.2017.07.008 28756304 Pavan Grandhi, T. S. et al. Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation. Biomaterials 142 , 171–185 (2017). 28756304 10.1016/j.biomaterials.2017.07.008

497. Wang W A native drug-free macromolecular therapeutic to trigger mutual reinforcing of endoplasmic reticulum stress and mitochondrial dysfunction for cancer treatment ACS Nano 2023 17 11023 11038 10.1021/acsnano.3c03450 37257082 Wang, W. et al. A native drug-free macromolecular therapeutic to trigger mutual reinforcing of endoplasmic reticulum stress and mitochondrial dysfunction for cancer treatment. ACS Nano 17 , 11023–11038 (2023). 37257082 10.1021/acsnano.3c03450

498. Zhang G Redox-responsive dendrimer nanogels enable ultrasound-enhanced chemoimmunotherapy of pancreatic cancer via endoplasmic reticulum stress amplification and macrophage polarization Adv. Sci. 2023 10 e2301759 10.1002/advs.202301759 PMC10460845 37350493 Zhang, G. et al. Redox-responsive dendrimer nanogels enable ultrasound-enhanced chemoimmunotherapy of pancreatic cancer via endoplasmic reticulum stress amplification and macrophage polarization. Adv. Sci. 10 , e2301759 (2023). 10.1002/advs.202301759 PMC10460845 37350493

499. Siwecka, N. et al. Dual role of endoplasmic reticulum stress-mediated unfolded protein response signaling pathway in carcinogenesis. Int. J. Mol. Sci . 20 , 4354 (2019). 10.3390/ijms20184354 PMC6770252 31491919

500. Chen L Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP Cell Death Dis. 2014 5 e1219 10.1038/cddis.2014.193 24810055 PMC4047922 Chen, L. et al. Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. Cell Death Dis. 5 , e1219 (2014). 24810055 10.1038/cddis.2014.193 PMC4047922