Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.

Introduction

Maintaining redox balance is crucial for normal cellular physiological functions. Composed of Trx, TrxR, and NADPH, the thioredoxin system functions as a core regulatory node fundamental to the preservation of cellular redox equilibrium [ 1 ]. The thioredoxin system plays a pivotal role in regulating major redox-dependent cellular processes, ranging from cell proliferation, migration, and cell death [ [2] , [3] , [4] ]. Beyond its involvement in multiple programmed cell death pathways, this system is also upregulated in response to diverse stress conditions, including oxidative damage, infection or inflammation, metabolic dysfunction, radiation, and chemical exposure [ 5 ]. Advances in understanding its physiological functions have further facilitated the development of related pharmaceuticals and therapeutic strategies. Research has now moved beyond traditional inhibitors (such as auranofin) to focus on developing novel compounds with high selectivity and low toxicity. Additionally, smart nanomaterials are being engineered to selectively deliver TrxR inhibitors to tumors. By combining them with therapies like chemotherapy or photothermal treatment, these systems effectively counteract drug resistance and limit systemic toxicity. The thioredoxin system features two principal isoforms, Trx-1 (cytosolic) and Trx-2 (mitochondrial), which are structurally conserved 12 kDa proteins containing a redox-active Cys-Gly-Pro-Cys (CGPC) motif [ 6 , 7 ] ( Table 1 ). This motif undergoes reversible oxidation–reduction cycles driven by electrons supplied by thioredoxin reductase and NADPH [ 12 , 13 ]. Trx functions as an efficient electron donor in its reduced state to reduce disulfide bonds or other oxidized moieties in target proteins, thereby regulating their activity and function [ 14 ] ( Fig. 1 ). Distinct Trx isoforms occur beyond the conventional cytoplasmic and mitochondrial types, existing in the endoplasmic reticulum, plasma membrane, and extracellular milieu [ 15 ]. Each of these variants possesses distinct structural characteristics and fulfills unique functional roles. For example, ER (endoplasmic reticulum)-resident Trx contains an N-terminal signal peptide directing it to the ER lumen, where it participates in protein folding and quality control, while the plasma membrane-associated form is a GPI-anchored truncation of cytosolic Trx [ [16] , [17] , [18] ]. Table 1 Thioredoxin and subtypes. Table 1 Name Location Ecoded Gene Monomer Structure Function Source Trx-1 Cytoplasm and nucleus of most mammalian cells TXN1 12 kDa Decreases oxidized proteins, influences transcription factors, controls cell growth and PCD, and defends against oxidative stress [ 8 ] Trx-2 Mitochondria of most mammalian cells TXN2 16 kDa Lowers oxidized proteins, sustains mitochondrial membrane potential, blocks mitochondrial permeability transition, defends against oxidative stress and apoptosis [ 9 ] Trx-3 Spermatozoids TXN3 13 kDa Directly catalyze Trx and reduced glutathione [ 10 ] Trx-80 Blood plasma and monocytes (secreted isoform derived from Trx-1) TXN1 10 kDa (generated by N-terminal truncation of Trx-1) Stimulates cytokine and complement production, enhances immune response, modulates cell proliferation and differentiation [ 11 ] Fig. 1 Diagram of the catalytic cycle and fundamental functions of the thioredoxin system. Schematic representation of the electron transfer reaction catalyzed by the TrxR homodimer. Reducing equivalents derived from NADPH are sequentially transferred to the flavin cofactor, then to the active-site disulfide of TrxR, and ultimately to the redox-active disulfide of Trx.

Thioredoxin reductases (TrxRs) are essential enzymes that use NADPH and flavin adenine dinucleotide (FAD) to catalyze the reduction of the disulfide bond in the thioredoxin active site [ 19 ]. The reduction of Trx is crucial, as it regenerates its active form, which functions as an indispensable reducing agent in a broad spectrum of biochemical processes. TrxR serves as a key regulator of essential cellular functions, such as redox balance, cell growth and death, and gene expression, by directly reducing target proteins [ 20 ]. Notably, adaptive overexpression of the thioredoxin system (Trx/TrxR) under oxidative stress is a common feature across multiple pathological conditions and has been strongly associated with cancer pathogenesis [ 21 ]. Dysregulation of the TrxR system contributes to the development of a broad spectrum of pathological conditions, such as cancer, infectious diseases, as well as cardiovascular and neurodegenerative disorders [ 15 , 21 , 22 ]. Given this broad pathological significance, key components of the thioredoxin signaling pathway have emerged as attractive therapeutic targets, especially in anticancer drug discovery. The initiation of clinical trials for the TrxR/Trx inhibitor Ethaselen marks a significant advancement in cancer therapy [ 23 ]. These findings clearly indicate that thioredoxin signaling pathways serve as effective drug targets.

In mammals, PCD plays a pivotal role in maintaining physiological balance by clearing damaged cells, facilitating tissue regeneration, and supporting developmental processes, which are orchestrated through sophisticated intracellular signaling networks [ [24] , [25] , [26] , [27] , [28] ]. These characteristics are observed in multiple tissues under both normal and specific pathological conditions [ 29 ]. Several decades of research have unveiled a smorgasbord of programmed cell death modalities and their corresponding signaling networks, including ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, mitochondrial permeability transition-triggered necrosis, and autophagy-dependent cell death [ [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] ]. The recent identification of cuproptosis and disulfidptosis offers new therapeutic approaches for tumors that are resistant to traditional treatments like chemotherapy and targeted therapy. These resistant tumors frequently lead to compromised antitumor immunity, a challenge that these novel cell death mechanisms may help to overcome [ 38 ]. The signaling pathways and regulatory networks, especially their interaction with other cell death mechanisms like apoptosis and pyroptosis, are actively being studied [ 39 , 40 ].

Exploring the regulatory networks of the thioredoxin system in disease is vital for developing rational therapies that modulate its function. In normal physiology, it sustains redox homeostasis and cell viability. Whereas in diseased states, its overactivation may enhance antioxidant capacity, promote malignant proliferation, and confer therapy resistance. This role-specific duality dictates that therapeutic approaches against the Trx system must be "bidirectional". Given that numerous forms of PCD are associated with oxidative damage, the thioredoxin system, as the principal antioxidant system, assumes a fundamental role in modulating these cell death pathways. This review synthesizes the regulatory mechanisms of the Trx system across various types of PCD and elucidates its contributions to various diseases and tumor therapy resistance, suggesting that targeting this system offers therapeutic promise. The development of Trx-targeting agents and their current status in clinical trials are also summarized.

The thioredoxin system and its cellular functions

The thioredoxin system and biological function

Thioredoxin-1 (Trx-1) exhibits a broad subcellular and extracellular distribution, localized within the cytoplasm, nucleus, and the extracellular milieu [ 41 ]. Predominantly cytoplasmic, Trx-1 functions as a central redox regulator, where it mitigates oxidative damage both by directly scavenging reactive oxygen species (ROS) and by maintaining intracellular redox homeostasis [ 42 ]. Beyond its antioxidant role, Trx-1 serves as an essential hydrogen donor for ribonucleotide reductase (RNR), supporting DNA synthesis by reducing nucleotides [ 43 ]. Trx-1 also modulates apoptotic signaling by binding to the N-terminal domain of apoptosis signal-regulating kinase 1 (ASK1), thereby suppressing ASK1-dependent apoptosis [ 44 ]. Under conditions such as oxidative stress, Trx-1 translocates into the nucleus through karyopherin-α-mediated nuclear import, thereby dynamically regulating transcriptional activity [ 45 ]. In the extracellular space, Trx-1 displays cytokine- and chemokine-like properties, participating in intercellular communication and immune modulation [ 46 ].

Trx-2, primarily localized in the mitochondria of metabolically active tissues, including the brain, liver, and heart, demonstrates greater stability than Trx-1 [ 47 ]. Beyond its antioxidant capacity like Trx-1, Trx-2 modulates mitochondrial membrane potential, supports electron transport chain activity, and regulates mitochondrial-dependent apoptosis. It also contributes to the protection of mitochondrial DNA (mtDNA) from oxidative damage and participates in mitochondrial protein folding and stability [ 7 , 48 ]. Trx-2 is associated with the development of various diseases, such as neurodegeneration and cardiovascular conditions [ 49 , 50 ].

TrxR, an essential antioxidant enzyme comprising three isozymes (TrxR1, TrxR2, and TrxR3), is sensitive to insufficient dietary selenium (Se) intake [ 51 ] ( Table 2 ). TrxR is an enzyme with wide substrate specificity capable of reducing multiple oxidizing substrates. Besides oxidized Trx, substrates include protein disulfide isomerase, glutaredoxin, glutathione peroxidase, hydrogen peroxide (H 2 O 2 ), lipid hydroperoxides, selenodiglutathione (GSSeSG), selenite, methylseleninate, selenocysteine, diphenylselenide, and ebselen [ [54] , [55] , [56] , [57] ]. Therefore, the Trx system is of paramount importance in redox regulation. Table 2 Thioredoxin reductase and subtypes. Table 2 Name Location Ecoded Gene Monomer Structure Function Source TrxR1 Cytoplasm TXNRD1 55 kDa Regulation of redox homeostasis; Control of cell growth and apoptosis; Modulation of early embryonic development; Participation in other physiological processes [ 11 ] [ 52 ] TrxR2 Mitochondria TXNRD2 55 kDa TrxR3 (TGR) Testicles TXNRD3 55-67 kDa Related to the maturation of sperm cells [ 53 ]

At the core of the Trx system is the NADPH-dependent reduction of oxidized Trx by TrxR, which drives the system's essential function in sustaining intracellular redox balance [ 58 ]. Trx regulates the structural and functional integrity of diverse substrate proteins by cycling between its reduced dithiol and oxidized disulfide states, thereby directly reducing disulfide bonds in target proteins [ 59 , 60 ]. This catalytic mechanism involves the formation of a transient mixed-disulfide intermediate between Trx and its substrate, followed by resolution catalyzed by TrxR, which regenerates reduced, active Trx [ 2 ]. Beyond protein disulfide reduction, Trx critically contributes to ROS scavenging by serving as an electron donor to peroxiredoxins (Prxs), thereby facilitating the decomposition of hydrogen peroxide, lipid hydroperoxides, and peroxynitrite [ 61 , 62 ]. Additionally, Trx supplies reducing equivalents to methionine sulfoxide reductases (Msrs), supporting the repair of oxidized methionine residues and mitigating oxidative protein damage [ 63 , 64 ]. Under conditions of oxidative stress, Trx becomes oxidized and dissociates from ASK1, thereby allowing ASK1 to activate downstream stress kinase cascades [ 65 , 66 ]. Through these integrated mechanisms, the Trx system exerts precise spatiotemporal control over cellular redox signaling, antioxidant defense, and adaptive stress responses, underscoring its central role in maintaining physiological redox homeostasis [ 55 ].

The thioredoxin system in redox homeostasis and antioxidant synergy

Trx collaborates with antioxidant enzymes such as glutathione peroxidase, superoxide dismutase (SOD), and catalase to efficiently neutralize ROS, thereby preventing oxidative damage and sustaining the organism's oxidative stress response [ 67 , 68 ]. To maintain the redox balance of antioxidant enzymes, Trx plays a vital role by increasing their catalytic efficiency [ 69 ]. This improvement allows for effective ROS detoxification, protecting aging cells from oxidative damage.

Trx acts as a critical protein repair enzyme that targets and reduces abnormal disulfide bonds formed during aberrant protein oxidation, utilizing NADPH as a reducing cofactor [ [68] , [69] , [70] ]. Functionally, Trx extensively intersects with the glutathione (GSH) system, coordinating cellular redox defense through multi-level crosstalk [ 70 ] ( Fig. 2 A). Although the Trx and GSH systems operate through distinct reductive pathways-the former utilizing TrxR and NADPH, and the latter relying on glutathione reductase (GR) and NADPH-they exhibit considerable functional crosstalk in collectively maintaining cellular redox homeostasis [ 71 ]. For instance, Trx can directly reduce oxidized glutathione (GSSG) through thiol-disulfide exchange, thereby assisting in the regeneration of reduced GSH [ 72 ]. Conversely, glutaredoxin (Grx), a GSH-dependent oxidoreductase, can partially substitute or complement Trx in reducing specific proteins or mixed disulfides [ 73 , 74 ]. Moreover, Trx enhances the antioxidant capacity of the GSH system by upregulating the activity of glutathione peroxidases (GPxs), which utilize GSH to detoxify hydrogen peroxide and lipid hydroperoxides [ [75] , [76] , [77] ]. Together, the Trx and GSH systems form an integrated redox network that synergistically strengthens the cell's ability to counteract oxidative stress and finely regulate redox-sensitive signaling pathways [ 78 ]. Fig. 2 Functional interplay between thioredoxin (Trx), glutathione (GSH), and peroxiredoxin (Prx). (A) The Trx system serves as a central hub in the cellular antioxidant defense, functionally intersecting with the GSH system and directly supporting key enzymes like superoxide dismutase SOD and catalase. Trx not only maintains the redox balance and catalytic activity of these enzymes by reducing oxidized cysteine residues but also provides a critical backup for H 2 O 2 clearance through GPx. This multi-level crosstalk forms a synergistic redox network that enhances the cell's capacity to neutralize ROS and fine-tune redox-sensitive signaling. (B) The Trx and GSH systems work synergistically to maintain intracellular redox homeostasis. In cancer therapy, inhibition of the Trx system can exert antitumor effects by inducing ROS accumulation, arresting the cell cycle, and activating ASK1-mediated apoptosis in cancer cells. However, the GSH system may compensate for this disruption, potentially attenuating the therapeutic outcome.

The Trx system acts as a key regulatory and integrative component of the cellular antioxidant network, enhancing the detoxification pathways facilitated by SOD and catalase [ 76 ]. SOD and catalase act in tandem to convert superoxide anions (O 2 − ) into water and oxygen, via the intermediate H 2 O 2 . The Trx system enhances the efficiency and stability of this defense mechanism [ 55 , 76 , 79 ]. Its role is multifaceted, operating at the level of enzyme maintenance, pathway reinforcement, and systemic integration. A key function involves the direct post-translational maintenance of the antioxidant enzymes themselves [ 80 ]. The activity of specific antioxidant enzymes, particularly SOD1 and catalase, can be modulated through a redox-sensitive mechanism involving the reversible oxidation of key cysteine residues [ 81 , 82 ]. The Trx system, via the powerful thiol-disulfide reductase activity of reduced Trx, acts as a redox-sensitive repair mechanism by reducing these aberrant oxidative modifications, thereby restoring the catalytic activity of these enzymes and sustaining the continuous detoxification flux of O 2 − to harmless end products [ 82 ].

Beyond direct enzyme maintenance, the Trx system provides an essential backup mechanism for H 2 O 2 clearance, predominantly through the thioredoxin-dependent peroxidase activity of Prxs [ 83 ]. This Prx-dependent pathway acts in concert with catalase, especially under conditions of high oxidative burden or when catalase capacity is saturated [ 84 ] ( Fig. 2 A). Prxs exhibit a high affinity for H 2 O 2 , making them particularly effective for managing signaling-related oxidant levels, while catalase handles bulk degradation [ 84 ]. The Trx system thereby amplifies the cell's capacity to manage the H 2 O 2 generated by SOD, preventing the accumulation of this potentially harmful metabolite, which could otherwise lead to the formation of highly reactive hydroxyl radicals via Fenton's reaction [ 85 , 86 ].

Trx system and reactive nitrogen species (RNS) are intricately interconnected, forming part of the cellular redox signaling network. Specifically, Trx can mediate transnitrosylation: by converting itself into S-nitrosothioredoxin (ONS-Trx-S 2 ), it reduces S-nitrosylated target proteins, facilitating the formation of intramolecular disulfide bonds and thereby releasing free NO or nitrosyl groups, which execute downstream signaling functions [ 87 , 88 ]. This mechanism is further elaborated in Section 2.4 .

The Trx system functions as a central integrator that orchestrates a broader antioxidant response. It maintains the redox environment necessary for the optimal operation of numerous cellular proteins. Its profound interconnection with the GSH system, including functional redundancies and cross-compensation with glutaredoxin, creates a robust buffering capacity for the entire redox network [ [89] , [90] , [91] ]. Trx plays a crucial role in modulating the activity of Nrf2 (nuclear factor erythroid 2 related factor 2), a key regulator of antioxidant gene expression [ 92 , 93 ]. Trx induces the dissociation of Nrf2 from its cytoplasmic inhibitor Keap1 through the reduction of specific cysteine residues on Nrf2 [ 94 , 95 ]. This reaction facilitates the nuclear import of Nrf2 and enhances its binding to DNA, thereby enabling robust transcription of target antioxidant genes [ 96 ]. Therefore, the Trx system is not merely an ancillary component but a fundamental regulator that provides critical pathways for peroxide elimination, and synchronizes the overall antioxidant defense to ensure robust protection against oxidative stress [ 97 ].

The thioredoxin system and regulation of redox-sensitive transcription factors

Trx-1 plays a pivotal role in modulating essential signaling pathways-including hypoxia and inflammatory responses-through its interactions with redox-sensitive proteins and transcription factors, such as redox factor-1 (Ref-1) and nuclear factor kappa B (NF-κB) [ 98 ]. Although predominantly localized in the cytosol, a fraction of Trx-1 translocates into the nucleus under specific conditions, enabling direct regulation of nuclear transcription factors [ 55 ]. This nuclear presence underpins its ability to fine-tune several key redox-sensitive transcription factors critical for cellular adaptation and stress responses. Firstly, Trx-1 reduces Ref-1, which in turn enhances the DNA-binding capacity of activator protein-1 (AP-1) by reducing a conserved cysteine within its DNA-binding domain. This mechanism is vital for AP-1 activation and the expression of its target genes [ 99 ]. Furthermore, the Trx-1/Ref-1 system is critical for the stabilization of HIF-1α [ 100 ]. After achieving stability, HIF-1α undergoes dimerization, enabling it to bind to hypoxia response elements (HREs) and orchestrate the expression of a genetic program that facilitates adaptation to low oxygen conditions [ 101 , 102 ].

The redox-regulated transcription factors AP-1 and HIF-1α, along with NF-κB, are all modulated by the cellular redox environment ( Fig. 2 B). Sequestered in the cytoplasm by its inhibitor IκB, NF-κB remains inactive until the IκB kinase (IKK) complex is activated, leading to IκB phosphorylation and degradation, and the subsequent release of NF-κB. A pro-oxidant state and cysteine oxidation promote NF-κB nuclear translocation, allowing for target gene regulations [ 101 , [103] , [104] , [105] ]. This process releases NF-κB, exposing its nuclear localization signal and promoting its nuclear translocation-a step facilitated by a pro-oxidative cytosolic environment and the oxidation of specific cysteine residues in NF-κB [ 106 , 107 ]. NF-κB requires reduction by Trx-1 to bind DNA effectively in the nucleus [ 108 ]. Conversely, diminished Trx expression enhances cellular susceptibility to oxidative stress-induced apoptosis by increasing the activation of pro-apoptotic proteins. Notably, Trx-1 deficiency upregulates a broad spectrum of genes, including those encoding anti-apoptotic proteins (e.g., Bcl-2, cIAPs), cyclins (e.g., Cyclin D1), and inflammatory cytokines [ 109 , 110 ]. Moreover, low Trx levels can suppress tumor development by inhibiting the function of various oncogenic proteins [ 111 ].

Trx-1 serves as a central redox hub that integrates cellular responses to hypoxia, inflammation, and oxidative stress by dynamically regulating the activity of key transcription factors. By modulating these pathways, Trx-1 not only fine-tunes adaptive gene expression and survival responses but also exerts dual physiological influence: it supports stress adaptation and redox homeostasis while constraining aberrant proliferation and apoptosis, thereby maintaining cellular and systemic functional integrity under fluctuating environmental challenges.

The post-transcriptional modifications of thioredoxin system

The critical role of protein post-translational modifications (PTMs) lies in their ability to regulate protein expression, localization, function, and interactions, making them a primary source of proteomic diversity and complexity [ 112 ]. The diverse biological functions of Trx-1 are finely regulated by a range of site-specific PTMs, including nitrosylation, glutathionylation, dimerization, intramolecular disulfide bond formation, phosphorylation, and nitration [ 113 ]. Together, these modifications constitute a multi-layered regulatory network.

Under highly oxidizing conditions, Cys62 and Cys69 among cysteine-specific modifications can form an intramolecular disulfide bond. This modification may contribute to Trx-1 inactivation under oxidative stress by impeding TrxR-mediated reduction of the active site [ 114 ]. S-nitrosylation can occur at Cys62, Cys69, or Cys73. While inhibiting the canonical reductase activity, modification at Cys69 enables transnitrosylation of target proteins such as caspase-3, thereby conferring anti-apoptotic activity independent of the reductase function [ 115 ]. Notably, only the disulfide form of Trx1 (with Cys32-Cys35 oxidized) is susceptible to nitrosylation. Glutathionylation at Cys73 inhibits enzymatic activity by preventing functional dimerization, and this reversible modification serves as an important functional interface between the thioredoxin and glutathione systems [ 116 ]. Nitrosoglutathione can induce either nitrosylation or glutathionylation, with the outcome likely determined by the nucleophilicity of the target cysteine [ 117 ]. Furthermore, certain nitrosylated sites may serve as precursors to glutathionylation [ 117 ]. Phosphorylation at threonine 100 (T100) attenuates the anti-apoptotic activity of Trx-1, suggesting that dephosphorylation at this site might serve as a potential focus for cancer therapy [ 118 ]. Lipid peroxidation-derived products such as 4-hydroxy-2-nonenal (HNE) covalently modify Trx-1, primarily at Cys73 in mammals, leading to loss of reductase activity and potential inhibition of TrxR [ 119 ]. Nitration at the sole tyrosine residue Tyr49 irreversibly inhibits both the reductive and anti-apoptotic functions of Trx-1. This modification is markedly enhanced in the aging heart following ischemia/reperfusion injury, and scavenging peroxynitrite can restore the cardioprotective function of Trx-1 [ 120 ]. Emerging research has identified a coenzyme A-mediated post-translational modification as an additional regulatory mechanism governing the thioredoxin system, thereby establishing a further protective pathway against ferroptosis [ 121 ].

In summary, Trx-1 integrates a dynamic, reversible, and context-dependent regulatory network through various PTMs at specific residues. These modifications not only regulate its classical disulfide reductase activity but also confer novel functions, including apoptosis regulation, signal transduction, and stress response. Potential crosstalk, competition, or synergy among different modifications allows Trx-1 to precisely respond to intracellular redox status, metabolic signals, and pathological stimuli, thereby playing a central role in maintaining cellular homeostasis and determining cell fate. This complex PTM-based regulatory framework underscores Trx-1's role as a signaling hub and identifies multiple potential therapeutic targets for diseases involving the Trx-1 pathway.

The role of thioredoxin system in programmed cell death

Apoptosis

Apoptosis, first described in 1972, is a type of cell death characterized by specific morphological alterations [ 122 , 123 ]. It plays essential roles in tissue homeostasis, development, and tumor biology. Apoptosis proceeds through two main pathways-intrinsic and extrinsic-both culminating in the activation of effector caspases [ [124] , [125] , [126] ]. These caspases execute the death program by cleaving key cellular substrates, leading to cell shrinkage, membrane blebbing, DNA fragmentation, and formation of apoptotic bodies [ 127 ].

A key consequence of inhibiting TrxR with electrophilic agents is the formation of SecTRAPs, which exacerbate oxidative stress and promote apoptosis [ 128 ]. This effect is often selectively toxic to cancer cells, which lack the protective low Trx system activity and strong Nrf2 response found in normal cells [ [129] , [130] , [131] ]. Nonetheless, the viability of some TrxR1-deficient cancers indicates that the role of TrxR in cell death is context-dependent, warranting deeper investigation [ 132 , 133 ] ( Fig. 3 ). SecTRAPs contribute to cytotoxicity by directly interfering with p53 activity and by acting in concert with (or directly enabling) p53-dependent death signals upon TrxR inhibition [ 134 , 135 ]. Many thioredoxin-targeting compounds induce tumor cell apoptosis by disrupting redox balance through p53-dependent mechanisms. This process is intensified through a self-amplifying cycle: TrxR inhibition and SecTRAP generation create a pro-oxidant state that drives further ROS accumulation, leading to apoptosis [ 136 , 137 ]. Fig. 3 Induction of apoptosis via inhibition of the thioredoxin system. Inhibition of the thioredoxin system induces severe oxidative stress, thereby activating established apoptotic pathways mediated by TrxR/Trx-ASK1/JNK and TrxR/Trx-p53. This process encompasses several critical intracellular events, including the generation of pro-oxidant SecTRAPs, post-translational modification of p53, and activation of ASK1.

Employing a yeast two-hybrid screen to probe for ASK1 interactors led to the identification of Trx-1 as a key negative regulator of ASK1 [ 138 ] (Fig. 2B and 3 ). In resting cells, ASK1 persistently associates with reduced Trx-1 to form an inactive complex. The binding of reduced Trx-1 to the N-terminus of ASK1 results in the inhibition of ASK1 signaling. Consequently, elevated Trx-1 levels suppress cancer cell apoptosis by inhibiting ASK1 [ 44 ]. However, oxidation of Trx-1 leads to its dissociation from ASK1, thereby activating ASK1 by converting it from its inactive to active kinase form [ 139 ]. For instance, the peptide Trx-1 inhibitor, 2GTP1, binds to Trx-1, disrupting its interaction with ASK-1. This disruption activates ASK-1 and its downstream pathways, leading to apoptosis in MDA-MB-231 cells [ 140 ]. Mitochondrial Trx2, analogous to its cytosolic counterpart Trx-1, has a vital function in suppressing ROS and regulating apoptosis through inhibition of the mitochondrial kinase ASK-1 [ 141 , 142 ]. As a key redox sensor, the ASK1-Trx-1 complex translates alterations in the cellular redox environment into downstream signaling pathways. This mechanism offers a promising avenue for identifying lead compounds that can specifically trigger cell death in cancer cells. In the context of neuronal injury, Trx-1 overexpression has been shown to significantly reduce apoptosis both in vivo and in vitro. Following controlled cortical impact (CCI), Trx-1 overexpression not only increased the baseline elevation of phosphorylated ATM (P-ATM) but did so without altering total ATM levels, underscoring the Trx-1-ATM-PPP axis as a potential therapeutic target for traumatic brain injury (TBI) [ 143 ]. Studies at different levels have demonstrated the protective effects of Trx system enhancement. At the cellular level, chrysophanol increased Trx-1 activity and suppressed JNK/Cx43 signaling, mitigating TGF-β-induced oxidative stress and apoptosis. Complementarily, in an in vivo aging model, a 10-week aerobic exercise program promoted Trx/TrxR expression in skeletal muscle, leading to increased Trx activity and suppression of apoptosis [ 144 ].

Initial studies indicated that Trx enhances p53's DNA-binding activity and further amplifies the Ref-1-mediated enhancement of p53 activity, suggesting a physiological role for Trx-dependent redox regulation in p53 signaling [ 145 , 146 ]. Posttranslational modifications tightly regulate the DNA binding and transcriptional activation of p53, which require a reducing cellular environment.

Disulfidptosis

Disulfidptosis, identified in 2023, is a newly recognized form of programmed cell death triggered by glucose deprivation in cells exhibiting elevated SLC7A11 (solute carrier family 7 member 11) expression [ 147 ]. The key drivers of disulfidptosis are excessive cystine import and constrained NADPH synthesis. This imbalance drives NADPH exhaustion, leading to abnormal disulfide cross-linking of actin filaments, the subsequent disintegration of the actin network, and, finally, cellular demise [ 148 ].

Recent studies indicate that disulfidptosis could significantly impact glucose metabolism disorders and related complications [ 149 ]. Trx functions to mitigate disulfide stress by modulating cysteine residues in protein complexes, offering protection against disulfidptosis. Notably, clinical evidence indicates that targeting this pathway helps preserve β-cell function, paving the way for novel interventions to enhance diabetes management [ 150 ]. A study demonstrated that NFATc1-driven upregulation of SLC7A11 creates a metabolic vulnerability to TrxR1 inhibitors during osteoclast differentiation. This indicates that TrxR1 inhibitors, known for treating osteoclast-related conditions, specifically target pre-OCs by causing intracellular cystine buildup and subsequent disulfidptosis [ 151 ]. Meanwhile, elevated TrxR1 expression is associated with poor prognosis in glioblastoma multiforme (GBM). Experimental evidence further indicates that glucose starvation-unlike oxygen or glutamine deprivation-induces TrxR1 upregulation in an Nrf2-dependent manner and sensitizes cells to TrxR1 inhibition-induced death. Notably, this study identifies TrxR1 as an inducer of disulfidptosis in GBM cells, thereby proposing TrxR1 targeting as a promising therapeutic strategy for this malignancy [ 152 ]. The findings from this research could guide therapeutic approaches for conditions involving oxidative damage, such as neurodegenerative and cardiovascular diseases ( Fig. 4 A). Fig. 4 The Role of Trx in disulfidptosis and ferroptosis. (A) Trx in disulfidptosis. Under glucose starvation or oxidative stress, Trx/TrxR1 activity influences disulfidptosis by modulating disulfide stress and SLC7A11-mediated cystine metabolism. (B) Trx in ferroptosis. Trx protects against lipid peroxidation through dual mechanisms: maintaining GPX4 activity and directly detoxifying lipid hydroperoxides via the Trx/TrxR system.

Several critical mechanistic questions concerning the specific role of the Trx system in disulfidptosis remain unanswered. For instance, does the collapse of the Trx system primarily trigger disulfidptosis, or is it a secondary consequence of a broader redox catastrophe? Are there specific, high-affinity protein substrates of the Trx system whose aberrant disulfide bonding directly initiates the lethal cascade, akin to the function of executioner caspases? Furthermore, how does the functional interplay between the cytosolic (TrxR1/Trx-1) and mitochondrial (TrxR2/Trx-2) arms of the system determine cell fate under disulfide stress? Determining whether the Trx system acts as a primary sensor, a key executioner, or a final failure point in this process is essential to clarify the fundamental nature of disulfidptosis as a regulated form of cell death or a metabolic collapse.

Ferroptosis

Characterized by iron-dependent lipid peroxidation, ferroptosis is a regulated cell death process first detailed in 2012 [ 153 ]. The process is initiated by excessive intracellular ferrous iron, which drives the Fenton reaction to generate ROS that subsequently oxidize membrane lipids [ [154] , [155] , [156] , [157] , [158] ]. The resultant accumulation of lipid peroxides, such as PLOOH, MDA, and 4-HNE, disrupts membrane integrity and leads to cell death. This process is counteracted by cellular antioxidant defenses, primarily the system Xc − -GSH-GPX4 axis, which reduces lipid peroxides [ [159] , [160] , [161] , [162] , [163] ]. Additional antioxidants, including CoQ 10 H 2 and BH4, also contribute to protection. Disruption of these antioxidant pathways initiates ferroptosis [ [164] , [165] , [166] , [167] , [168] ].

The Trx system constitutes a crucial defense mechanism against ferroptosis. It contributes to this protective role through dual, complementary mechanisms: indirectly, by sustaining the cellular reducing environment required for optimal glutathione peroxidase 4 (GPX4) activity, and more directly, via the Trx/TrxR/Prx axis, which actively detoxifies specific lipid hydroperoxides [ 169 ]. In a Parkinson's disease model, overexpression of Trx-1 in mice counteracted the reduction of GPX4 induced by the neurotoxins MPP + (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium), while in vitro experiments confirmed that both ferrostatin-1 and Trx-1 overexpression alleviate GPX4 deficiency and MPP + -mediated toxicity, supporting Trx-1's involvement in ferroptosis protection [ 170 , 171 ]. Recent studies have elucidated the pivotal role of the Trx system in regulating ferroptosis across different cancer contexts. Yang et al. demonstrated that auranofin induces ferroptosis and promotes lipid peroxidation at a high dose (25 mg/kg) by inhibiting TrxR activity. This finding provides compelling evidence that TrxR is a key regulator of ferroptosis and identifies auranofin as a novel dual activator of both hepcidin expression and ferroptosis through distinct mechanisms [ 172 ]. In lung adenocarcinoma (LUAD), Bian et al. further revealed that RARA suppresses ferroptosis by upregulating Trx, suggesting that targeting the RARA-Trx/PPM1F axis may enhance the efficacy of ferroptosis inducers (FINs) or chemotherapy [ 173 ]. Complementing this, recent findings indicate that Trx itself participates in a complex with SMARCA4 and ALDH16A1, which dually regulates Trx stability and function to control ferroptosis. Notably, this regulatory axis is also implicated in chemotherapy and immunotherapy resistance in SMARCA4-deficient non-small cell lung cancer (NSCLC), highlighting the Trx system as a central node that influences therapeutic response across multiple modalities [ 174 ]. Together with NADPH, the Trx system reduces disulfide bonds in target proteins, such as peroxiredoxins, reactivating them and protecting cells from oxidative damage [ 175 ] ( Fig. 4 B). Recent work further indicates that Coenzyme A protects against ferroptosis via CoAlation of mitochondrial TrxR, adding another layer of redox-mediated regulation [ 121 ].

Autophagy

Autophagy is the primary intracellular degradation mechanism that transports and breaks down cytoplasmic materials in the lysosome [ 176 ]. During autophagy, autophagy-related proteins orchestrate the formation of a double-membrane autophagosome that sequesters cytoplasmic components. The subsequent fusion of the autophagosome with lysosomes enables the degradation of the encapsulated cargo by lysosomal hydrolases [ 177 , 178 ]. The basal level of autophagy maintains cellular homeostasis, but changes in autophagy can lead to disease pathogenesis, such as cancer [ 179 , 180 ] ( Fig. 5 A). Fig. 5 The role of Trx in various programmed deaths Trx regulates PCD by modulating the activity and expression of multiple PCD-related proteins. (A) Trx promotes autophagosome initiation and maturation by regulating multiple autophagy-related proteins, thereby activating the autophagy process. (B) Trx inhibits MLKL phosphorylation, which suppresses membrane rupture and necroptotic cell death. (C) Trx negatively regulates inflammasome activation through caspase inhibition, thus preventing GSDMD cleavage and pyroptotic cell lysis in response to danger signals sensed by Pyrin/NLRP1/NLRP3/NLRP4.

In diabetic retinopathy (DR), autophagy and exosome secretion in photoreceptor and retinal pigment epithelial (RPE) cells are critically involved in the pathogenesis of the disease. The upregulation of Trx ameliorates photoreceptor degeneration in diabetes by enhancing AMPK-mediated autophagy and exosome release, thereby providing a protective mechanism against diabetic retinal damage. This cellular crosstalk is further evidenced by the engulfment and degradation of photoreceptor-derived exosomes by RPE cells in the DR context [ 181 ]. Trx upregulation safeguards cochlear hair cells from diabetes-induced reduction. The underlying mechanisms involve the regulation of ER stress through the ASK1 and mitochondrial pathways, as well as the control of autophagy via thioredoxin interacting protein (TXNIP) [ 182 ]. Also, Trx-1 may enhance the autophagy-lysosome pathway to eliminate α-syn in PD mice. The study revealed that Trx-1 overexpression inhibited acrylamide(ACR)-induced autophagy in PC12 cells, whereas Trx-1 downregulation promoted autophagy triggered by ACR in these cells [ 183 , 184 ]. Furthermore, the natural product isowalsuranolide (Hdy-7) was shown to promote lysosomal biogenesis and induce autophagy through inhibition of TrxR [ 185 ].

Necroptosis

First identified in 2005, necroptosis is a regulated form of necrosis that can be triggered by apoptotic ligands when caspase-8 is inhibited, functioning as an alternative death pathway [ 186 , 187 ]. Necroptosis is executed by the core necroptotic effector proteins: receptor-interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). Phosphorylation of MLKL by RIPK3 serves as a critical step in necroptosis, inducing the formation of disulfide-linked MLKL polymers that are necessary for plasma membrane disruption and cell death [ 188 , 189 ]. Shikonin induces ROS-dependent necroptosis in cancer cells by inhibiting TrxR1 and promoting redox cycling. [ 190 ]. A recent study identified chelerythrine as a novel TXNRD1 inhibitor that targets the Sec498 residue. This inhibition induces necroptosis, thereby exerting significant anti-tumor effects across a range of gastric cancer cell lines [ 191 ]. The study found that necrosulfonamide, a compound modifying MLKL, cross-links cysteine 86 of human MLKL with cysteine 32 of the thiol oxidoreductase Trx-1. Additionally, shRNA-mediated Trx-1 knockdown enhances MLKL polymerization and increases cell sensitivity to necroptosis. PX-12, an inhibitor of Trx-1, triggers necroptosis across various cancer cell lines, highlighting Trx-1's role as a key regulator that prevents cell death by keeping MLKL in a reduced, inactive form [ 192 ] ( Fig. 5 B).

Pyroptosis

Mediated by various inflammasomes and executed by caspases and gasdermin (GSDM) proteins, pyroptosis is a pro-inflammatory programmed cell death pathway discovered in 1989 [ 193 ]. The upstream signaling events that trigger it can be subdivided into several pathways, including the canonical, non-canonical, caspase-3/8-induced, and granzyme (GZM)-mediated pathways [ 187 ]. A key sensor in the canonical pathway is NLRP1 (NOD-like receptor family pyrin domain-containing 1), the inaugural inflammasome component to be discovered. While this pathway's physiological role is to combat infections and support adaptive immunity, its hyperactivation is implicated in pathological conditions such as autoinflammatory disorders and cancer [ 194 ] ( Fig. 5 C). Cellular assays demonstrate that Trx inhibits NLRP1 inflammasome activation, thereby negatively regulating NLRP1. This conclusion has been confirmed in various diseases. Sepsis, a frequent complication of infections, greatly affects the survival of critically ill patients. The study demonstrated that TrxR1 inhibition hinders OMV internalization by preserving Trx-1 in its oxidized state, thereby limiting Caspase-11 activation and mitigating sepsis [ 4 ]. Research has revealed that Trx-1 confers neuroprotection in models of Alzheimer's disease through a novel mechanism: the reduction of NLRP1-dependent neuronal pyroptosis. This pathway identifies Trx-1 as a promising candidate for therapeutic intervention [ 195 ]. Besides, Trx-1 suppresses NLRP3-mediated pyroptosis by modulating TXNIP expression and its interaction with NLRP3 in AD models [ 196 ]. All these findings confirm the close relationship between Trx system and pyroptosis, demonstrating its potential to provide new therapeutic strategies for various diseases.

Various PCD mechanisms do not act as isolated routes but rather as threads in a highly coordinated cellular tapestry. In this intricate network, specific death pathways can be selectively activated, silenced, or their signals rerouted, with the ultimate functional outcome being dictated by a set of master molecular switches and convergent signaling nodes. Inhibition of Trx leads to cystine accumulation, thereby increasing susceptibility to disulfidptosis. NADPH metabolism plays a decisive role in disulfidptosis, and suppression of the Trx system exacerbates NADPH depletion, further promoting this form of cell death. Concurrently, ROS accumulation resulting from Trx inhibition may also contribute to ferroptosis. Under normal conditions, high expression of SLC7A11 promotes cystine uptake and glutathione synthesis, thereby suppressing ferroptosis. However, under glucose starvation and insufficient NADPH, high SLC7A11 expression leads to cystine accumulation and induces disulfidptosis. Conversely, low SLC7A11 expression promotes ferroptosis but reduces the possibility of disulfidptosis [ 197 ]. Trx is also associated with several other PCD core protein molecules, which may directly influence the mode of cell death. Trx can inhibit p53 transcriptional activity, thereby promoting ferroptosis through a dual mechanism: transactivation of pro-apoptotic target genes and direct suppression of the cystine/glutamate antiporter system (system Xc − ). This mechanism may directly steer cells toward either apoptosis or ferroptosis. Once activated, caspase-8 cleaves and activates downstream effector caspases, such as caspase-3, initiating the execution phase of apoptosis. Simultaneously, it cleaves key necroptosis proteins, RIPK1 and RIPK3, thereby suppressing necroptosis. When caspase-8 is inhibited, the suppression of RIPK1/RIPK3 is relieved, leading to a shift in the cellular response towards necroptosis [ 198 ].

Interaction between Trx and various diseases

The thioredoxin system plays a vital role in maintaining cellular stability by participating in key processes such as redox balance, cell cycle control, and gene regulation, thereby exerting a profound influence on cell proliferation and survival [ 2 ]. Trx and TrxR are crucial for cellular function, as their knockout leads to embryonic lethality in mouse models [ 199 , 200 ]. The thioredoxin system is crucial for cellular redox signaling, regulating the activity of various transcription factors. The malfunction of this system is closely associated with various systemic diseases. We herein systematically discuss the associations between the Trx system and five major disease categories: malignancies, infections, neurodegenerative conditions, cardiovascular diseases (CVDs), and metabolic diseases [ 49 ]. The dynamics of Trx expression reflect a cellular homeostatic response to oxidative stress. Although acutely upregulated as a protective mechanism, persistent Trx overexpression in chronic conditions like cancer and inflammation can become maladaptive, actively driving disease progression. The expression of Trx is often upregulated in cancers, inflammatory conditions, and cardiovascular pathologies. Conversely, it is commonly associated with downregulation or functional impairment in neurodegenerative and metabolic diseases ( Fig. 6 ). Fig. 6 Thioredoxin system dysfunction links to a spectrum of systemic diseases. Trx system maintains cellular homeostasis by regulating redox balance, cell cycle progression, and transcription factor activity. Trx expression is frequently upregulated in cancer (A), infectious disease (C), and cardiovascular disease (E), where it supports survival and can drive progression. In contrast, its downregulation or functional impairment is associated with neurological disease (B) and metabolic disease (D). This disease-specific expression pattern underscores the dual nature of Trx as both a protective agent and a pathological driver, highlighting its central role in disease mechanisms and therapeutic targeting across multiple organ systems.

The thioredoxin system and cancer

Redox signaling is implicated in virtually all recognized hallmarks of cancer. As a master regulator of cellular redox balance, the thioredoxin system is pivotal in orchestrating these signals, thereby contributing to multiple aspects of tumorigenesis and cancer progression. [ 1 , 2 , 56 ]. The rapid division and aberrant proliferation of malignant cells lead to a marked dependence on the thioredoxin system, resulting in its frequent overexpression in tumor cells [ 2 ]. The Trx/TrxR system plays a dual role in cancer. On the one hand, it plays a crucial protective role in normal cells; on the other hand, its overexpression and heightened activity in cancer cells are widely recognized as a hallmark of cancer, promoting tumor initiation, progression, invasion, and drug resistance through multiple mechanisms [ 201 , 202 ]. Numerous clinical studies demonstrate that Trx and TrxR are frequently overexpressed in various cancers, correlating with poor prognosis, reduced survival, and resistance to chemotherapy [ 203 , 204 ].

The thioredoxin system promotes cell proliferation and inhibits cell death

The Trx/TrxR system significantly enhances the proliferative and survival capacity of cancer cells by providing robust antioxidant defense [ 55 , 205 ]. Cancer cells produce elevated ROS levels due to increased metabolic activity [ 206 ]. The Trx/TrxR system effectively mitigates ROS, safeguarding cancer cells from oxidative stress-related damage and death, thereby providing a notable survival benefit [ 202 ]. Additionally, the system modulates essential pro-proliferative signaling pathways by regulating transcription factors such as NF-κB, AP-1, and HIF-1α [ 207 , 208 ]. This results in the increased expression of genes linked to cell proliferation, survival, angiogenesis, and metastasis. Concurrently, it suppresses tumor suppressors like p53; reduced Trx binds to p53, thereby indirectly inhibiting its pro-apoptotic activity [ 200 ].

At the transcriptional level, the reduced form of Trx1 translocates to the nucleus where it directly reduces critical cysteine residues in several redox-sensitive transcription factors, thereby modulating their DNA-binding affinity and transactivation potential. A prominent example is NF-κB, the regulatory mechanisms of which have been detailed in preceding sections [ 209 ]. At the post-translational and signaling level, the Trx system exerts direct inhibitory control over core apoptotic machinery. The most characterized mechanism involves ASK1 [ 65 ]. Beyond ASK1, the Trx system also regulates other apoptotic components, such as by reducing and inactivating phosphatase and tensin homolog (PTEN), a key tumor suppressor, thereby sustaining the pro-survival PI3K/Akt signaling axis [ 210 ]. Inhibition of the Trx system can synergize with GPX4 suppression to robustly induce ferroptosis, underscoring its essential and non-redundant role in preventing this form of cell death-a mechanism particularly relevant in cancer [ 170 ].

In summary, the Trx system promotes tumor proliferation and survival through a multi-layered strategy: it activates pro-growth and adaptive transcriptional programs (via NF-κB, HIF-1α), directly inhibits core apoptotic initiators (like ASK1), dampens tumor suppressor pathways (like PTEN), and fortifies cells against novel forms of programmed death (like ferroptosis). This integrated network ensures that cancer cells can thrive under the very conditions of metabolic and oxidative stress that would normally trigger their demise.

The thioredoxin system reshapes tumor metabolism

Trx is the main electron donor for RNR, the enzyme that limits the rate of de novo deoxyribonucleotide (dNTP) synthesis, which is crucial for DNA replication and repair [ 211 ]. Thus, the Trx system directly supports the rapid proliferation of cancer cells by fueling DNA synthesis. It has been demonstrated that the thioredoxin system governs sensitivity to checkpoint kinase 1 inhibitors (CHK1i) by modulating ribonucleotide reductase activity via redox mechanisms [ 43 ]. Disruption of Trx1 or TrxR1 increases replication stress (RS) by suppressing the RNR redox cycling, leading to depletion of the dNTP pool. Following thioredoxin system inhibition, RRM1 (ribonucleotide reductase subunit M1) oxidation increases, and CHK1i disrupts the RRM2 pathway, resulting in severe impairment of RNR function and thereby promoting synergistic lethality. The mechanism by which Trx inhibitors, when combined with CHK1i, suppress cancer cell growth involves modulating cysteine oxidation of RRM1. This finding suggests that developing inhibitors targeting the thioredoxin system holds significant promise, either as monotherapy or in combination with other targeted therapies.

The thioredoxin system promotes invasion and metastasis

The Trx/TrxR system promotes angiogenesis by activating transcription factors HIF-1α and NF-κB, leading to the expression of pro-angiogenic factors like VEGF. This process stimulates the formation of new tumor vasculature, supplying nutrients and oxygen for tumor growth [ 56 ]. Cancer cells sustain epithelial-mesenchymal transition (EMT) under enhanced stress conditions partly through the protective effects of antioxidant systems. Elevated activity of the thioredoxin (Trx/TrxR) and glutathione (GSH/Grx) systems mitigates intracellular oxidative stress, thereby preserving the redox-sensitive signaling required for EMT. This protection enables the activation of key transcription factors such as Twist and Snail, which promote the loss of epithelial traits and the acquisition of a migratory, invasive phenotype, ultimately facilitating cancer cell invasion and metastasis [ 212 ]. It also indirectly facilitates extracellular matrix degradation by inhibiting tissue inhibitors of metalloproteinases (TIMPs), thereby paving the way for metastasis [ 201 ].

The thioredoxin system mediates therapy resistance

The ability of cancer cells to employ the Trx system to defend against ROS toxicity has made it a key factor in chemotherapeutic resistance. It contributes to chemotherapy resistance because many chemotherapeutic agents, such as cisplatin and anthracyclines, rely on generating ROS to kill cancer cells [ 213 , 214 ]. The overexpression and hyperactivation of the Trx/TrxR system effectively neutralize these ROS, diminishing the efficacy of chemotherapeutic drugs and leading to resistance [ 202 , 204 ]. PX-12, an inhibitor of Trx-1, showed a synergistic effect with trastuzumab in breast cancer cells resistant to treatment. The combination therapy of PX-12 and trastuzumab significantly reduced cell viability and suppressed survival signals, including phosphorylated Akt and Bcl-2, while concomitantly enhancing oxidative stress and apoptosis; these effects were more pronounced in resistant cells [ 215 ]. PX-12 enhanced doxorubicin's growth-inhibitory effects in diffuse large B-cell lymphoma (DLBCL) cells and amplified 2-DG-induced cytotoxicity in colorectal cancer models, both in vitro and in vivo [ 216 , 217 ]. The novel dual-gold(I) agent QB1561 overcomes drug resistance by concurrently inhibiting TrxR activity and impairing mitochondrial respiratory function [ 218 ]. Similarly, it contributes to radiotherapy resistance, as the therapeutic effect of radiation is partly dependent on ROS generation [ 219 ]. Ultimately, it enhances anti-apoptotic effects by inhibiting the ASK1-p38/JNK apoptosis pathway via reduced Trx binding to ASK1 and by upregulating additional anti-apoptotic proteins, thereby increasing cancer cell resistance to treatment-induced apoptosis [ 111 , 220 ]. In conclusion, the involvement of Trx in conferring resistance to anticancer therapies presents a compelling clinical rationale for targeting this system to improve treatment outcomes.

The thioredoxin system and infectious diseases

The thioredoxin system plays a role in infectious diseases, notably in HIV infection [ 221 ]. Extracellular thioredoxin, mainly secreted by antigen-presenting cells and specific T cells, markedly enhances CXCR4 (C-X-C chemokine receptor type 4) co-receptor expression on CD4 + T cells [ 222 ]. As CXCR4 is one of the principal co-receptors for HIV entry (particularly for X4-tropic virus strains), Trx enhances the chemotaxis and infection efficiency of HIV toward T cells by increasing receptor availability, thereby promoting viral dissemination [ 223 ]. Additionally, the Trx system is crucial in preventing apoptosis in infected cells. HIV infection induces oxidative stress, which would normally trigger apoptosis to limit viral replication [ 224 ]. However, the HIV Tat protein potently upregulates host Trx production [ 225 , 226 ]. Elevated levels of reduced Trx bind to and inhibit ASK1, blocking its downstream pro-apoptotic p38 MAPK and JNK signaling pathways [ 138 ]. This suppression of apoptosis prolongs the survival of infected CD4 + T cells, transforming them into persistent, highly productive viral reservoirs that dramatically enhance viral replication and spread [ 227 ]. Trx influences viral gene expression by utilizing its redox activity to regulate transcription factors like NF-κB and AP-1, which interact with the HIV LTR (long terminal repeat) promoter [ [228] , [229] , [230] ]. Studies also indicate that elevated Trx levels may indicate EBV infection or T-cell activation/transformation status [ 231 , 232 ]. Serum Trx levels in HCV-infected (hepatitis C virus) patients correlate with increased serum ferritin levels and liver fibrosis progression [ 233 ].

Given the direct dependence of diverse parasites, such as worms and filamentous species, on the thioredoxin system for survival, and the common presence of both Sec-dependent and Sec-independent TrxR isoforms among them, it is not surprising that targeting TrxR has emerged as a promising anti-parasitic strategy [ 234 , 235 ]. The strategy's relevance is further supported by the system's importance in inflammatory lung conditions, where it contributes to the chronic inflammation underlying diseases like neonatal lung disease [ 236 , 237 ].

The thioredoxin system in neurodegenerative diseases

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are defined by progressive neuronal dysfunction and loss. Although the precise mechanisms underlying neurodegeneration are not fully elucidated, oxidative stress is well-established as a key contributor. It is implicated in inducing mitochondrial and endoplasmic reticulum dysfunction, processes that ultimately lead to neuronal death [ 238 ]. The Trx system is a key defense mechanism in the brain against oxidative stress, inflammation, and apoptosis. In neurodegenerative diseases, its decreased or insufficient function renders neurons more vulnerable to attacks by toxic proteins (such as Aβ and α-synuclein) and inflammatory factors, thereby accelerating neuronal death and disease progression [ 195 , 239 ]. Therefore, enhancing the function of the Trx system is considered a highly promising strategy for preventing and treating these diseases.

Research indicates that brain tissues in AD patients exhibit reduced levels of Trx, highlighting its significant role in AD [ 240 ]. In AD, Aβ oligomers induce oxidative stress and may directly inhibit Trx activity, while impaired Trx function exacerbates the toxicity of both Aβ and hyperphosphorylated Tau [ 241 ]. Clinical studies indicate that reduced Trx expression and activity in the brains of AD patients correlate with disease severity, while Trx overexpression in AD mouse models enhances cognitive function and mitigates pathological features [ 242 ]. In PD, oxidative stress promotes α-synuclein aggregation into Lewy bodies, a process counteracted by the Trx system. Dopaminergic neurons in the substantia nigra are particularly susceptible to damage from ROS produced during dopamine metabolism, and Trx plays a vital role in their survival [ 243 ]. Research indicates reduced Trx levels in the substantia nigra of Parkinson's disease patients, while Trx inducers or mimetics in PD models offer neuroprotection and improve motor symptoms [ 244 ]. In amyotrophic lateral sclerosis (ALS), oxidative stress and aberrant protein aggregation contribute to pathogenesis. Mutant SOD1, which is prone to oxidative modification, is implicated in familial ALS, and Trx may modulate its toxic function [ 245 ]. Enhancing the Trx system in ALS models has demonstrated therapeutic potential, suggesting a protective role across these major neurodegenerative disorders [ 246 ]. Collectively, the evidence supports that dysfunction, whether acquired or genetic, in Trx or TrxR can result in neuronal degeneration [ 247 ].

Protective roles of the thioredoxin system in cardiovascular diseases

Trx plays a crucial protective role in cardiovascular diseases by mitigating oxidative stress and inflammation, which are key contributors to their pathogenesis [ 248 ]. Trx's antioxidant properties help maintain redox balance, thereby protecting cardiac cells from oxidative damage. Additionally, Trx modulates signaling pathways involved in cell survival and apoptosis, further contributing to cardiovascular protection. Its proper function is essential for maintaining vascular endothelial function, cardiomyocyte survival, and overall cardiac performance [ 249 ]. In conditions like atherosclerosis, myocardial infarction, and heart failure, the Trx system's activity is compensatorily increased to safeguard the heart. Nevertheless, its inadequacy or depletion may hasten disease progression [ 22 ]. Therefore, enhancing the function of the Trx system through pharmaceuticals or biological agents represents a highly promising novel strategy for preventing and treating cardiovascular diseases.

In atherosclerosis, Trx exerts protective effects by counteracting oxidized low-density lipoprotein (ox-LDL) through inhibiting endothelial cell apoptosis and inflammatory responses induced by ox-LDL [ 250 ]. Homocysteine-induced oxidative stress, through the downregulation of Trx-1, likely prompts the upregulation of TrxR to mitigate hydroperoxides and lipid peroxides linked to atherosclerosis [ 251 ]. Studies indicate that NADPH oxidase activation, along with reduced Trx and eNOS (endothelial NO synthase) activity, links elevated homocysteine levels to oxidative stress and endothelial dysfunction [ [252] , [253] , [254] ]. Elevated plasma levels of Trx in atherosclerosis patients may serve as a biomarker, reflecting a compensatory response to ongoing oxidative stress [ 50 ]. In myocardial ischemia/reperfusion injury, a well-studied context for Trx function, reperfusion following ischemia produces substantial ROS, causing significant damage. Trx plays a central mediating role in cardioprotective strategies such as pre- and post-conditioning, and activation of the Trx system significantly alleviates reperfusion injury [ 22 , 255 , 256 ]. In heart failure, chronic oxidative stress and inflammation drive disease progression. While the Trx system is typically activated in the failing heart as an adaptive response to persistent stress, it may eventually become depleted or functionally inadequate, making enhancement of Trx activity a promising therapeutic strategy [ 257 , 258 ]. In hypertension, where oxidative stress disrupts endothelial function and promotes vasoconstriction, Trx helps maintain normal vascular tone and blood pressure by preserving NO (Nitric Oxide) signaling and suppressing vascular inflammation [ 259 , 260 ]. In diabetic cardiomyopathy, chronic hyperglycemia leads to significant oxidative stress, and the Trx system is crucially protective of cardiomyocytes against diabetes-induced damage [ 261 , 262 ].

The thioredoxin system in metabolic disease

The Trx system is fundamentally involved in metabolic regulation, with its function being critical for maintaining redox balance and controlling inflammation. Dysregulation of this system contributes to the pathogenesis of several metabolic disorders, including type 2 diabetes mellitus (T2D), insulin resistance, and non-alcoholic fatty liver disease (NAFLD) [ 57 , 97 ].

In type 2 diabetes, the Trx system is crucial for safeguarding pancreatic β-cells, which are naturally susceptible to oxidative stress due to their limited antioxidant capacity. Chronic hyperglycemia (glucotoxicity) induces excessive ROS production, leading to β-cell dysfunction and apoptosis. The Trx system counteracts this by providing essential antioxidant defense, thereby helping to preserve insulin secretory function [ 263 ]. Consistent with this, studies in diabetic animal models demonstrate that Trx overexpression or administration of Trx inducers (e.g., Irisin) improves hyperglycemia and insulin sensitivity, whereas Trx deficiency accelerates disease progression [ 264 , 265 ]. Regarding insulin resistance, Trx protects key insulin-responsive tissues-including the liver, skeletal muscle, and adipose tissue. Its mechanisms involve neutralizing ROS, inhibiting protein tyrosine phosphatase 1B (PTP1B), and attenuating inflammatory signaling. These actions collectively improve insulin responsiveness and promote glucose absorption and utilization [ 266 , 267 ]. In NAFLD, which progresses from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, Trx mitigates hepatic steatosis and inflammation. It achieves this by lowering oxidative stress and lipotoxicity, blocking lipid peroxidation, and reducing the creation of pro-inflammatory cytokines, thus aiding in the prevention of the progression to NASH [ 268 ]. Furthermore, through its antioxidant activity, Trx may inhibit the activation of hepatic stellate cells, suggesting potential anti-fibrotic effects [ 269 , 270 ]. Obesity, a key driver of metabolic dysregulation, is characterized by adipose tissue expansion (particularly visceral fat), which significantly elevates oxidative stress and chronic inflammation [ 271 ]. Trx is expressed in adipose tissue, and reduced Trx activity exacerbates adipose dysfunction and local inflammation, thereby further promoting systemic insulin resistance [ 272 , 273 ].

Summary of clinical applications involving the Trx system

The Trx system as a promising biomarker

The upregulation of Trx expression and activity is a well-documented response to oxidative stressors, including H 2 O 2 , ultraviolet radiation, and inflammatory signals. This characteristic makes Trx a sensitive indicator of oxidative stress and reflects its critical role in maintaining redox homeostasis, modulating signaling pathways, and providing antioxidant defense [ 274 ]. In cancer, one of the most extensively studied fields, Trx is significantly overexpressed in various malignancies, such as liver, pancreatic, colorectal, lung, and cervical cancers. This elevated level is not only associated with tumor proliferation, invasion, metastasis, and chemotherapy resistance, indicating a poor prognosis, but also makes the Trx system a key therapeutic target [ 274 ]. In cardiovascular diseases characterized by oxidative stress, elevated plasma levels of Trx in patients with acute coronary syndromes or heart failure may serve as an independent predictor of disease severity and the risk of future adverse cardiovascular events [ 251 ]. For inflammatory and autoimmune diseases like rheumatoid arthritis and lupus, elevated Trx levels in blood and affected tissues reflect inflammatory activity and may help monitor treatment response [ 236 ]. Dysregulation of the brain thioredoxin system is increasingly recognized as a marker of oxidative stress and plays a significant role in the underlying pathology of neurodegenerative diseases such as AD and PD [ 240 , 275 ]. Similarly, in diabetes, changes in the Trx system, particularly in patients with vascular complications, highlight its potential role in assessing the risk of developing these serious comorbidities [ [263] , [264] , [265] , [266] , [267] ]. TrxR emerges as a promising biomarker, supplementing the conventional panel to improve risk stratification and severity assessment in rheumatoid arthritis (RA).

TrxR is proposed as a prognostic marker in hepatocellular carcinoma (HCC). Substantial evidence indicates that serum TrxR activity is significantly elevated in HCC patients and may outperform the conventional biomarker alpha-fetoprotein (AFP), particularly in diagnosing AFP-negative cases. Consequently, the measurement of serum TrxR activity has emerged as a potent auxiliary tool for diagnosis, risk stratification, and prognosis evaluation in HCC [ 276 ]. Besides, evaluated by key diagnostic metrics, including sensitivity and specificity, TrxR exhibited greater discriminatory power than AFP, CEA (carcinoembryonic antigen), and CA19-9 (carbohydrate antigen 19-9) for the detection of liver cancer versus healthy controls [ 277 ]. Serum TrxR activity is strongly associated with HCC malignancy, with significantly elevated levels observed in patients experiencing recurrence and those who do not survive [ 278 ]. Assaying plasma TrxR activity serves as a non-invasive tool not only for the early detection of gastrointestinal malignancies but also for monitoring therapeutic responses [ 279 ]. TrxR is also an effective parameter in the diagnosis of gynecologic cancers and breast cancer. Furthermore, its activity level shows significant promise as a biomarker for evaluating treatment response [ 280 , 281 ]. Emerging evidence suggests that Trx-1 and TrxR1 are promising candidate biomarkers for the clinical diagnosis of brain tumors [ 282 ]. Plasma TrxR activity serves as a convenient, non-invasive, and effective adjunct to diagnosis for NSCLC, especially in distinguishing metastatic status and histological subtypes [ 283 ]. The 6-week post-treatment change in TrxR activity, alongside other clinical and hematological biomarkers, could effectively predict treatment outcomes and prognosis in NSCLC patients undergoing combination immunotherapy with PD-1 inhibitors [ 284 ].

Therefore, analyzing Trx/TrxR activity or expression in biological samples could significantly enhance future disease diagnosis and treatment.

Targeting the Trx system for therapeutic intervention

The Trx system's pivotal role in disease pathogenesis has made the development of its inhibitors or activators a key focus in drug discovery. Maintaining precise redox control is essential for cell survival, since excessive activity or deficiency in redox systems can promote disease. Given the centrality of Trx system, targeting it has prompted two key strategies: inhibiting Trx/TrxR (e.g., PX-12 or auranofin) for cancer therapy, while boosting Trx activity shows promise for neurodegenerative. However, solitary inhibition risks compensatory activation, underscoring the need for combinatorial approaches to overcome resistance. In the core area of anticancer drug development, the strategy focuses on inhibiting the Trx system to disrupt redox balance in cancer cells, thereby enabling selective elimination [ 1 ]. Ruthenium and gold-based compounds, like auranofin, target the active site of TrxR, inducing lethal oxidative stress in cancer cells [ 285 ]. Another notable example is arsenic trioxide, highly effective against acute promyelocytic leukemia, partly due to its inhibition of TrxR [ 286 ]. Currently, numerous TrxR inhibitors are in preclinical or early-stage clinical trials, highlighting this pathway as a major direction in anticancer research. Conversely, a therapeutic strategy for inflammatory diseases involves the development of recombinant human Trx or its analogs, which have demonstrated benefits in animal models of conditions such as ischemia-reperfusion injury, acute lung injury, and arthritis [ 169 ] ( Fig. 7 ). Fig. 7 Targeting the thioredoxin system by natural molecules as a therapy strategy. The Trx system has emerged as a promising therapeutic target due to its central role in regulating cellular redox homeostasis. Current investigational agents include natural products, synthetic compounds, nanomedicine-based delivery systems, and recombinant proteins. Activation of the Trx system demonstrates protective effects in neurodegenerative diseases, cardiovascular diseases (CVDs) and metabolic diseases, primarily by mitigating oxidative stress and cellular damage. Conversely, inhibition of this system exhibits therapeutic potential in malignancies and certain infectious diseases by disrupting redox balance and inducing selective cytotoxicity in pathological cells. This dual-role approach highlights the context-dependent utility of Trx system modulation in diverse disease pathologies.

Trx inhibitors as potential therapeutic agents

Targeting the Trx represents a promising avenue for therapeutic intervention. This approach targets cysteine residues within its functional domains: the catalytic site (Cys32, Cys35) and the allosteric regulatory site (Cys62, Cys69, Cys73) [ 287 , 288 ] ( Table 3 ). Tabel 3 Clinical studies on the inhibition of thioredoxin (Trx) for cancer therapy. Tabel 3 Drug Study Title Study Number Conditions Status Period of study PX-12 • Phase II Study of PX-12 in Patients With Advanced Pancreatic Cancer NCT00417287 Pancreatic Neoplasms TERMINATED a 2006.12-2009.04 • A Trial of PX-12 in Patients With a Histologically or Cytologically Confirmed Diagnosis of Advanced or Metastatic Cancer NCT00736372 Metastatic Cancer, Advanced Cancer COMPLETED 2008.06-2009.08 Dimethylfumarate (DMF) • Dimethyl Fumarate, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme NCT02337426 Adult Brain Glioblastoma, Adult Giant Cell Glioblastoma, Adult Gliosarcoma COMPLETED 2015.02-2017.11 • Study on Therapy With Dimethylfumarate in Patients With Cutaneous T Cell Lymphoma (CTCL) NCT02546440 Cutaneous T Cell Lymphoma COMPLETED 2015.09-2022.09 a The study was terminated early due to a lack of significant antitumor activity and unexpectedly low baseline levels of Trx-1.

The anti-proliferative compound PX-12 was discovered through a screen of disulfide compounds [ 289 ]. It functions via binding to the Cys73 residue of Trx-1, thereby inhibiting its reduction by TrxR1. The antitumor effects of PX-12 were examined using a mouse model of colitis-associated cancer (CAC) induced by AOM/DSS (azoxymethane/dextran sodium sulfate). The study demonstrates that PX-12 effectively inhibits STAT3 (signal transducer and activator of transcription 3) activation and reduces the progression of AOM/DSS-induced CAC in mice [ 290 ]. PX-12 sensitizes AML cells to arsenic trioxide, thereby enhancing apoptosis induction. PX-12 demonstrated efficacy in suppressing the growth of bortezomib-resistant myeloma cells and reversing their drug resistance, as validated in both in vitro and in vivo settings. Furthermore, it exhibited significant antitumor activity in an osteosarcoma model by inducing cell death and suppressing metastatic progression [ 291 ]. Following a Phase I trial, the Phase II evaluation of PX-12 in pancreatic cancer ( NCT00417287 ) was terminated early due to low Trx-1 expression and inefficacy [ 292 ]. The study was discontinued early due to a lack of meaningful clinical efficacy and low baseline Trx-1 levels, indicating that PX-12 is ineffective in unselected patients with advanced pancreatic cancer who have received prior treatments. The potential clinical application of PX-12 in cancer patients is yet to be determined.

Dimethyl fumarate (DMF), an FDA-approved therapy for multiple sclerosis (MS), has demonstrated efficacy beyond its approved use and shows potential as a therapeutic agent for inflammatory resolution [ 293 ]. DMF treatment modifies Cys73 in Trx-1, akin to PX-12 treatment. Research suggests that targeting Trx-1 activity offers a new strategy for treating tumors reliant on NF-κB. T-cell lymphoproliferative disorders such as T-ALL (T cell acute lymphoblastic leukemia) and CTCL (cutaneous T-cell lymphoma) are characterized by constitutive NF-κB activation, which is essential for their survival. This dependency makes NF-κB a compelling therapeutic target, as its inhibition triggers cell death. DMF acts on this pathway by targeting Trx-1, a critical regulator of NF-κB, thereby suppressing NF-κB activity [ 294 ]. Results from the NCT02337426 trial confirmed that DMF was well tolerated in combination with the standard Stupp regimen in newly diagnosed GBM patients [ 295 ]. The NF-κB inhibitor DMF has demonstrated efficacy as a novel treatment for primary CTCL in a phase II clinical study. Further evaluation is underway in a phase III study, real-life patient care, and combination therapies ( NCT02546440 ) [ 296 ].

The small molecule PMX464 (formerly AW464) acts as a strong Trx-1 inhibitor by targeting all five cysteine residues, including the active site Cys32 and Cys35 [ 297 ]. Its anti-tumor activity demonstrates a pronounced conditional dependency: while minimally effective in normoxic environments, it exhibits significant cytotoxicity under hypoxia in colon carcinoma cells, with fibroblasts and endothelial cells displaying higher resistance. Research in colorectal and breast cancer models supports its anti-proliferative properties [ 298 ], highlighting the need for dose optimization to exploit its selective action in hypoxic tumors.

By inhibiting chromatin condensation and facilitating histone acetylation, histone deacetylase inhibitors (HDACis) such as SAHA and sodium butyrate enhance transcriptional activity. Notably, this activity can indirectly target the thioredoxin system for cancer therapy. In prostate cancer cells, SAHA induces TXNIP expression, thereby inhibiting Trx-1 and promoting oxidative stress [ 299 ]. In colon carcinoma models, sodium butyrate selectively impairs Trx-1 activity via HDAC inhibition and TXNIP upregulation, an effect that sparingly affects normal cells [ [300] , [301] , [302] , [303] ]. Importantly, the tumor-suppressive potential of this Trx-1 inhibitory mechanism has been confirmed in vivo. Therefore, exploiting HDACis to inhibit Trx-1 indirectly offers a viable therapeutic avenue.

Diterpenoids are a class of 20-carbon terpenoids built from four isoprene units. Isoforretin A (Iso A), a diterpenoid isolated from the Chinese medicinal herb Isodon forrestii var. forrestii [ 304 ], functions as a Trx-1 inhibitor. Its activity elevates intracellular ROS, leading to oxidative stress that culminates in cell death. In models of colon carcinoma, Iso A was shown to suppress Trx-1 activity, accompanied by chromatin condensation and fragmentation, resulting in cell death. Similarly, allitridin (diallyl trisulfide), an organosulfur compound derived from garlic via the hydrolysis of allicin, also targets Trx-1. It directly conjugates to the active-site cysteine residues (Cys32 and Cys35) through a Michael addition reaction. Given the importance of Trx-1 in breast cancer metastasis, a key driver of death in TNBC (Triple negative breast cancer), it has been shown in nude mouse models that diallyl trisulfide targets Trx-1 and consequently inhibits metastasis [ 305 ].

Glutaredoxins play a central role, in concert with thioredoxins, in reducing disulfide bonds and reversing oxidative protein damage. Structurally, Grx contains an active-site disulfide bridge and utilizes glutathione as a cofactor. In humans, the Grx system comprises four main isoforms: Grx1 (cytosol, mitochondrial intermembrane space, nucleus), Grx2 (cytosol, mitochondria, nucleus), Grx3 (cytosolic and nuclear), and Grx5 (cytosolic and mitochondrial) [ 306 ]. In contrast to the thioredoxin system, which depends on TrxR for regeneration, Grx is reduced directly by glutathione rather than a dedicated reductase [ 74 ]. This functional overlap enables Grx to compensate for Trx activity when TrxR is inhibited, making dual inhibitors of Trx and Grx of considerable clinical interest [ 19 ]. A notable example is eprenetapopt (APR-246), developed as a p53 reactivator, which also inhibits Trx-1 and Grx1, though the therapeutic significance of this activity remains under investigation [ 307 , 308 ]. However, the contribution of this dual inhibition to its overall antitumor effect requires further clarification. Thiotert, a 6-dithio-2-deoxyguanosine analog, induces ROS accumulation and oxidative stress, leading to apoptosis in MDS (myelodysplastic syndrome) and lymphoma cells by inhibiting Trx-1 and TERT [ 309 ]. Iron chelation therapy has been shown to benefit multiple clinical endpoints in MDS, an effect at least partially attributed to the mitigation of iron-induced oxidative stress by chelators [ 310 ]. Given that the use of iron chelators is limited by side effects such as renal toxicity and gastrointestinal adverse reactions, it would be worthwhile to explore whether inhibition of Trx could exert a synergistic therapeutic effect [ 311 ].

The primary consequence of Trx inhibition is a marked increase in intracellular ROS levels, which subsequently induces multiple cell death pathways [ 312 ]. Well-characterized or newly developed small-molecule inhibitors represent powerful tools for probing the mechanisms of Trx-dependent cell death.

TrxR inhibitors as therapeutic agents

Indeed, the current literature describes a greater number of thioredoxin reductase inhibitors than thioredoxin inhibitors, largely because TrxR is a more favorable target for anticancer drug development. This preference is driven by the frequent upregulation of TrxR in various cancers, which has generated significant interest in its therapeutic exploitation. Structurally, the N-terminal redox-active site (Cys59/Cys64) is sterically hindered, making it less suitable for targeting by inhibitors. In contrast, the C-terminal region of mammalian TrxR contains a unique selenocysteine residue (Sec498) that forms a redox center with a neighboring cysteine (Cys497) via a selenenylsulfide bond. This C-terminal motif is solvent-exposed and structurally more accessible, making it a highly attractive and druggable site for the rational design of specific inhibitors [ 1 , 204 ] ( Table 4 ). Tabel 4 Clinical studies on the inhibition of TrxR for cancer therapy. Tabel 4 Drug Study Title Study Number Conditions Status Period of study Azelaic Acid • Study to Evaluate the Feasibility of Twice Daily Use of Topical Azelaic Acid in Breast Cancer Patients Undergoing Radiation NCT06966388 Breast Cancer RECRUITING 2025.08- Arsenic trioxide (ATO) • Evaluate the Efficacy and Safety of Interferon- Combined With ATO in the Treatment of Arsenic-resistant APL NCT06450145 Tumor RECRUITING 2024.05- • Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer NCT06088030 Pediatric Cancer, Li-Fraumeni Syndrome, p53 Mutations RECRUITING 2023.12- • Oral-ATO for TP53-mutated Myeloid Malignancies NCT06778187 Acute Myeloid Leukemia, Myelodysplastic Neoplasm, Chronic Myelomonocytic Leukemia, TP53 Gene Mutation, Arsenic Trioxide RECRUITING 2025.02- • Frontline Oral Arsenic Trioxide for APL NCT04687176 Acute Promyelocytic Leukemia RECRUITING 2021.01- • Arsenic Trioxide With MAPK Inhibitors and Chemotherapy for Stage 4/M Neuroblastoma NCT06933394 Neuroblastoma RECRUITING 2025.05- • Fuzuloparib Arsenic Trioxide Platinum Resistance Relapsed Ovarian Cancer NCT04518501 Efficacy and Safety RECRUITING 2020.07- • Tretinoin and Arsenic Trioxide With or Without Gemtuzumab Ozogamicin in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia NCT01409161 Acute Promyelocytic Leukemia With PML-RARA RECRUITING 2011.10- • Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia NCT04793919 Acute Promyelocytic Leukemia RECRUITING 2019.10- • RWE of 1st Line Treatment With ATO/ATRA for Adult APL NCT04897490 Promyelocytic Leukemia, Adult Acute RECRUITING 2021.03- Auranofin • Auranofin PK Following Oral Dose Administration NCT02089048 Amoebiasis COMPLETED 2014.04-2015.05 • Phase I and II Study of Auranofin in Chronic Lymphocytic Leukemia NCT01419691 Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Leukemia, Prolymphocytic COMPLETED 2011.09-2015.09 • Auranofin for Giardia Protozoa NCT02736968 Amoebic Dysentery, Giardiasis COMPLETED 2016.11-2021.03 • Auranofin in Decreasing Pain in Patients With Paclitaxel-Induced Pain Syndrome NCT02063698 Pain COMPLETED 2014.02-2016.11 • Auranofin in Treating Patients With Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer NCT01747798 Recurrent Fallopian Tube Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Primary Peritoneal Cavity Cancer COMPLETED 2012.11-2015.04 • Sirolimus and Auranofin in Treating Patients With Advanced or Recurrent Non-Small Cell Lung Cancer or Small Cell Lung Cancer NCT01737502 Extensive Stage Small Cell Lung Carcinoma, Lung Adenocarcinoma, Recurrent Non-Small Cell Lung Carcinoma, Recurrent Small Cell Lung Carcinoma, Squamous Cell Lung Carcinoma, COMPLETED 2014.05-2023.04 • Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure NCT02961829 Chronic Infection, HIV COMPLETED 2015.07-2020.03 • A Proof-of-concept Clinical Trial Assessing the Safety of the Coordinated Undermining of Survival Paths by 9 Repurposed Drugs Combined With Metronomic Temozolomide (CUSP9v3 Treatment Protocol) for Recurrent Glioblastoma NCT02770378 Glioblastoma COMPLETED 2016.11-2020.12 Curcumin • Curcumin Supplementation in Cervical Cancer NCT06080841 Locally Advanced Cervical Cancer RECRUITING 2023.04- • Adjuvant Curcumin to Assess Recurrence Free Survival in Patients Who Have Had a Radical Prostatectomy NCT02064673 Prostate Cancer RECRUITING 2014.05- • Trial of Curcumin to Prevent Progression of Low-risk Prostate Cancer Under Active Surveillance NCT03769766 Prostate Cancer RECRUITING 2019.03- • Concomitant Curcumin Palliative Radiotherapy in Advanced Cervical Cancer Trial NCT05947513 Cervical Cancer RECRUITING 2025.04- • Study Investigating the Ability of Plant Exosomes to Deliver Curcumin to Normal and Colon Cancer Tissue NCT01294072 Colon Cancer RECRUITING 2011.01- • Curcumin and Piperine in Patients on Surveillance for Monoclonal Gammopathy, Smoldering Myeloma or Prostate Cancer NCT04731844 Prostate Cancer, Multiple Myeloma, Smoldering Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance RECRUITING 2021.12- • Safety of Anal Curcumin NCT06626230 Anal High Grade Squamous Intraepithelial Lesion RECRUITING 2025.03- • The Thoracic Peri-Operative Integrative Surgical Care Evaluation Trial - Stage III NCT04871412 Lung Cancer, Gastric Cancer, Esophageal Cancer RECRUITING 2022.04- • Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms NCT06063486 Clonal Cytopenia of Undetermined Significance, Essential Thrombocythemia, Myelodysplastic Syndrome, Myelofibrosis, Polycythemia Vera RECRUITING 2024.03- • A Study of a Plant-Based Diet and Dietary Supplements in People With Smoldering Multiple Myeloma NCT06055894 Multiple Myeloma, Smoldering RECRUITING 2023.09- • A Feasibility Study Evaluating a Role for Maintenance Therapy in Patients With Biochemically Progressive Castration Sensitive Prostate Cancer on Intermittent Androgen Deprivation Therapy NCT06044025 Castration Sensitive Prostate Cancer RECRUITING 2024.04- • A Study Comparing a Plant-Based Diet With Supplements and Placebo in People With Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Multiple Myeloma NCT05640843 Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma RECRUITING 2022.11- • Study of Liposomal Curcumin in Combination With RT and TMZ in Patients With Newly Diagnosed High-Grade Gliomas NCT05768919 Glioblastoma RECRUITING 2023.03- • Study of the Effect of a Nutritional Supplement on Microbiota, Metabolic Control, Inflammatory Profile, and Quality of Life in Patients With Polycystic Ovary Syndrome. NCT06551285 Polycystic Ovary Syndrome, Metabolic Syndrome RECRUITING 2024.02- Ethaselen • Ethaselen for the Treatment of Thioredoxin Reductase High Expression Advanced Non-small Cell Lung Cancers NCT02166242 Carcinoma, Non-small Cell Lung COMPLETED 2014.06-2021.12 Abbreviations: ATO, Arsenic trioxide; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; RWE, real-world evidence; MGUS: Monoclonal Gammopathy of Undetermined Significance; TMZ, temozolomide; RT, radiotherapy.

Azelaic acid, a nine-carbon straight-chain dicarboxylic acid, demonstrates broad-spectrum antitumoral potential in vitro, exhibiting antiproliferative and cytotoxic effects across multiple tumor cell lines. One of its main mechanisms of action is the inhibition of mitochondrial oxidoreductases, such as FAD/NAD(P)H-dependent enzymes like TrxR1, which disrupts cellular energy metabolism [ 313 ]. In cultured melanoma cells, azelaic acid has been shown to suppress DNA synthesis and reduce cell proliferation without impairing protein production, indicating a selective inhibitory effect on abnormal melanocyte growth [ 314 ]. The compound, formulated as a 20% cream, is approved for treating acne vulgaris in dermatology, owing to its anti-inflammatory and antimicrobial effects [ 315 ]. It has also shown efficacy in treating lentigo maligna, inducing lesion remission in clinical settings [ 316 ]. Furthermore, azelaic acid alleviates AIC3-induced toxicity by modulating oxidative stress and inflammatory markers-including malondialdehyde, carbonyl proteins, TNF-α (tumor necrosis factor α), IL-1β (interleukin 1β), NF-κB, and GSK-3β-thereby mitigating neurocognitive deficits and hippocampal molecular alterations in rodent models [ 317 ]. Its long carbon chain structure has prompted speculation regarding its potential utility in multiple sclerosis therapy [ 318 , 319 ]. Given its low toxicity, non-teratogenicity, and non-mutagenicity, azelaic acid is a promising dual-action candidate that merits further clinical research in cancer and neurological diseases. Although it is known to act as an oxidoreductase inhibitor, its precise molecular mechanism remains to be elucidated [ 320 ].

Arsenic trioxide (ATO) is an approved anticancer agent that functions in part by inhibiting TrxR1 [ 286 ]. It is most prominently utilized in acute promyelocytic leukemia (APL), a malignancy in which ATO significantly contributes to remission induction and survival. Landmark clinical trials have solidified the combination of ATO with all-trans retinoic acid (ATRA) as a standard, highly effective treatment for newly diagnosed APL, significantly enhancing cure rates [ 321 ]. Beyond APL, preclinical evidence suggests broader antitumor potential; in a p53 R279W mutant mouse model prone to spontaneous tumors, ATO administered via drinking water extended survival by reactivating mutant p53 [ 322 ]. In contrast, the therapeutic use of ATO in neurological contexts remains experimental. One recent study reported that pretreating neuroblastoma cells with lycopene enhanced antioxidant enzyme activity and reduced oxidative stress in ATO-exposed cells, suggesting that lycopene may serve as a neuroprotective adjuvant in ATO-based regimens [ 323 ]. While ATO is firmly established in cancer therapy, its application in neurological diseases requires further mechanistic and clinical investigation before it can be considered a first-line treatment option.

The novel thioredoxin reductase inhibitor A-Z2 was synthesized by conjugating azelaic acid to organic arsenicals, yielding agents with enhanced potency and reduced toxicity. This compound triggers intrinsic apoptosis and demonstrates efficacy in treating AML [ 324 ]. Various metal-based compounds that modulate thioredoxin reductase activity have been widely applied in anticancer treatment, among which platinum and gold complexes hold particular importance [ 1 , 204 ]. Gold complexes, due to their unique electronic structures, can inhibit reduced biomolecules like TrxR. A prominent example is auranofin (AF), a highly potent TrxR inhibitor [ 325 , 326 ]. Similarly, platinum-based agents such as cisplatin and carboplatin irreversibly inhibit TrxR [ 325 ]. These metal complexes exhibit strong selectivity for TrxR, without affecting other reductases such as glutaredoxin and glutathione reductase. This selectivity arises from the strong affinity of platinum complexes for the selenocysteine residue in the TrxR active site, rather than the cysteine thiols found in related enzymes. Such inhibition occurs effectively in both cytosolic and mitochondrial TrxR isoforms [ 209 ]. The consequent disruption of cellular redox homeostasis triggers substantial ROS accumulation, leading to lipid, protein, and DNA damage. Specifically, mitochondrial TrxR2 inhibition exacerbates ROS generation and impairs mitochondrial integrity. Accompanying dysfunction of the electron transport chain further amplifies oxidative stress and compromises cellular energy production [ 327 , 328 ].

Auranofin induces ROS accumulation in colorectal carcinoma cells, thereby enhancing their sensitivity to radiation. This radiosensitization effect leads to cell death primarily through ROS-mediated DNA damage [ 329 , 330 ]. In addition to its radiosensitizing effects, Auranofin also suppresses key malignant behaviors, including proliferation, invasion, and metastasis, with direct evidence from colon carcinoma mouse models [ 331 ]. Data from colon organoids are also noteworthy. Research demonstrated that cancer organoids exhibited a significantly stronger response to auranofin than organoids from healthy tissue [ 332 ]. Auranofin triggers ROS accumulation and inhibits glycolysis in lung carcinoma cells, resulting in cell death [ 333 ]. Auranofin enhances the efficacy of other agents when used in combination. Auranofin has demonstrated notable anticancer effects against various blood cancers, including myeloma, leukemia, and lymphoma [ 334 ]. Besides, recent studies have explored auranofin's potential to combat breast cancer in both in vitro and in vivo settings [ 335 , 336 ]. Meanwhile, auranofin has also been demonstrated to induce apoptosis in lung cancer, thereby overcoming chemoresistance and enhancing the efficacy of chemotherapeutic drugs [ 337 , 338 ]. Ongoing clinical studies are investigating auranofin for the treatment of several malignancies, including chronic lymphocytic leukemia ( NCT01419691 ), ovarian cancer ( NCT01747798 , NCT03456700 ), and recurrent lung cancer ( NCT01737502 ), following encouraging earlier findings [ 339 ]. Data are preliminary and have not yet been published in a peer-reviewed journal.

Sourced from the turmeric plant ( Curcuma longa , Zingiberaceae), curcumin exhibits significant anti-inflammatory and anticancer activities [ 340 ]. Curcumin has been shown to inhibit NF-κB and TrxR [ 341 ]. The anti-tumor activity of curcumin is mediated through its inhibition of TrxR. This inhibition occurs by binding to the enzyme's active site, disrupting NADPH-dependent electron transfer and leading to ROS accumulation in cancer cells. This elevated oxidative stress consequently suppresses metastasis, triggers cell death, and enhances radiosensitivity [ 342 ]. Its low water solubility limits curcumin's potential clinical applications. Consequently, analogs such as WZ26 have been developed to inhibit TrxR, thereby limiting tumor cell proliferation and survival [ 343 , 344 ]. These efforts underscore the ongoing interest in leveraging curcumin's pharmacological potential through structural optimization.

Sourced from the long pepper plant ( Piper longum L.), the alkaloid piperlongumine exhibits inhibitory activity against TrxR [ 345 ]. The anticancer effect of piperlongumine is mediated by ROS accumulation, leading to DNA damage, induction of apoptosis, and radiosensitization [ 346 ]. These investigations were performed in vitro using cell lines. Studies show that oxaliplatin not only enhances the antitumor effect of 5-FU (5-fluorouracil) in a colon cancer mouse model but also reverses 5-FU resistance in human colorectal cancer by promoting intracellular ROS accumulation [ 347 ]. Besides, piperlongumine has been shown to inhibit glioblastoma multiforme proliferation by inducing ferroptosis in both in vitro and in vivo models [ 348 ]. Further research is needed to assess the potential of piperlongumine for tumor treatment and clinical application, given the limited data available.

Isodeoxyelephantopin (IDET) is a compound derived from Elephantopus scaber L., a plant in the tropical Asteraceae family known for its anticancer properties [ 349 ]. IDET suppresses TrxR and increases ROS levels, triggering JNK pathway activation and apoptosis [ 350 ]. The combination of buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that reduces GSH levels, and IDET synergistically triggers apoptosis. Treatment with IDET, alone or in combination with cisplatin, has been shown to reduce colorectal tumor growth in a mouse model [ 349 ]. A key mechanism underlying the synergistic anti-tumor effects of the IDET and paclitaxel combination involves inhibition of STAT3 phosphorylation [ 351 ]. The organoselenium TrxR inhibitor Ethaselen induces intrinsic apoptosis and shows broad antitumor activity [ 352 ]. A completed Phase I trial ( NCT02166242 ) in high-TrxR NSCLC awaits results on survival and safety. In gastric cancer, it synergizes with oxaliplatin via ROS induction and TrxR1 inhibition [ 353 ]. BS1801 is a new small-molecule agent that targets the Cys497/Sec498 active site of TrxR1, effectively inhibiting its enzymatic function through competitive binding. Treatment with BS1801 elevates intracellular ROS levels, triggers apoptosis in glioblastoma cells, and activates ER stress, thereby overcoming temozolomide (TMZ) resistance. These actions contribute to the potent anti-glioma efficacy of BS1801, highlighting its promising clinical translational potential [ 354 ].

In summary, this article has reviewed a range of natural compounds with inhibitory activity against the Trx/TrxR system. These agents hold great promise as lead compounds for the rational design of novel therapeutics.

The recombinant Trx proteins represent promising therapeutic drugs

The recombinant Trx protein demonstrates significant therapeutic potential across multiple medical fields, primarily focused on mitigating diseases driven by excessive oxidative stress and inflammation [ 355 ]. The recombinant Trx protein demonstrates therapeutic potential for impeding the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) by mitigating oxidative stress and inflammatory responses [ 356 ]. Although significant obstacles remain in its translation into a conventional therapeutic, including a short half-life, difficulties in drug delivery, and complex manufacturing processes, this approach represents a novel treatment strategy that targets the root causes of diseases, namely oxidative stress and inflammation, endowing it with substantial development value and broad clinical application prospects.

Conclusion and perspective

The maintenance of redox homeostasis, critically regulated by the thioredoxin system, is vital for mitigating oxidative stress and supporting signaling fidelity [ 357 ]. An imbalance can contribute to cellular dysfunction and cancer development [ 55 ]. Notably, cancer cells exploit this system by enhancing antioxidant defenses, including the thioredoxin system, to counteract their intrinsically high ROS levels, thereby promoting proliferation and survival [ 102 , 111 ]. This dependency renders the thioredoxin system a compelling target for anticancer therapy.

Thioredoxin reductase is essential for all biochemical pathways utilizing Trx as a reducing agent. These pathways participate in various physiological and pathological processes [ 190 ]. TrxR contains two essential redox sites: the first site, located near the FAD cofactor and involving a pair of cysteine residues, accepts electrons from NADPH. The second redox site, situated at the C-terminal region, consists of a selenocysteine-cysteine pair that relays electrons from the first site to the substrate Trx [ 358 ]. Owing to the requirement for full functional integrity at both redox centers to reduce Trx, TrxR presents multiple potential binding sites for inhibitory compounds. This distinctive structural and catalytic property, along with its common dysregulation in disease states, collectively underscores the pharmacological value of targeting this enzyme [ 359 , 360 ]. However, the rational design and evaluation of dual-action pharmacophore inhibitors that simultaneously engage both active sites remain a significant challenge in drug development. This review critically reassesses the literature on the rationale for targeting TrxR in pharmaceutical applications.

In summary, a comprehensive understanding of the functional interplay between the Trx system and PCD is essential for developing effective Trx-related therapies. The Trx system sustains redox homeostasis and protects against oxidative stress, yet it also critically governs cell survival and death. While its ability to suppress PCD is physiologically protective, tumors often exploit this mechanism to evade apoptosis and promote angiogenesis, thereby accelerating progression and metastasis. Conversely, enhancing Trx activity holds therapeutic potential for neurodegenerative and ischemic diseases, highlighting its context-dependent role. Therefore, Trx-targeted interventions must be precisely designed to either inhibit pathological overactivity or restore dysregulated signaling, all while preserving its vital physiological functions. However, translating this knowledge into clinically viable therapies faces significant challenges. Achieving target specificity is complicated by the existence of multiple Trx isoforms-such as cytosolic/nuclear Trx-1 and mitochondrial Trx-2, which share high structural homology within the thioredoxin superfamily. Designing isoform-selective modulators that avoid disrupting systemic redox balance remains difficult. Functional redundancy with the glutathione system further increases the risk of off-target effects and may trigger compensatory resistance mechanisms, such as upregulation of parallel antioxidant pathways. Moreover, the narrow therapeutic window of Trx inhibition raises safety concerns, as excessive suppression can induce systemic oxidative damage, leading to potential cardiac, neurological, or hepatic toxicity. From a translational perspective, the absence of validated predictive biomarkers hampers patient stratification, while suboptimal pharmacokinetics-including poor solubility, low oral bioavailability, and rapid metabolism-limit drug efficacy and clinical applicability. To advance the field, future efforts should prioritize: 1) Developing isoform-selective and context-aware modulators of the Trx system; 2) Exploring rational combination strategies, such as coupling Trx inhibition with ferroptosis inducers or immunotherapies; 3) Engineering intelligent delivery systems to enhance tumor selectivity and reduce systemic toxicity; 4) Expanding therapeutic applications beyond oncology to inflammatory, fibrotic, and degenerative diseases.

Ultimately, a central goal is to redefine the Trx system from a broadly targeted anticancer agent into a dynamically monitorable and precisely tunable master regulator of cellular fate. Interdisciplinary collaboration and technological innovation will be crucial to fully elucidate the Trx-PCD axis, paving the way for the next generation of precision therapeutics in oncology and beyond.

Ethics approval and consent to participate

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research was supported by the Construction Fund of Key Medical Disciplines of Hangzhou ( 2025HZZD01 , 2025HZGF04 ), 10.13039/501100001809 National Natural Science Foundation of China (No. 82202429 ). 10.13039/501100017594 Medical and Health Science and Technology Project of Zhejiang Province (Grant No. 2025KY125 ).

CRediT authorship contribution statement

Yunyi Wu: Writing – original draft. Yue Su: Writing – original draft. Feifan Pan: Writing – original draft. Feifan Jin: Writing – review & editing. Hangqi Huang: Writing – review & editing. Aoli Deng: Writing – review & editing. Yajuan Lu: Resources. Yi Lu: Resources. Tiexin Li: Resources. Jing Du: Conceptualization, Supervision. Xiangmin Tong: Conceptualization, Supervision. Yanchun Li: Conceptualization, Supervision.

Declaration of competing interest

The authors declare that there is no conflict of interest.

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Abbreviations:

ACR acrylamide AD Alzheimer’s disease ADCD autophagy-dependent cell death AF auranofin AFP alpha-fetoprotein AKI acute kidney injury ALS amyotrophic lateral sclerosis AML acute myeloid leukemia AOM/DSS azoxymethane/dextran sodium sulfate AP-1 activator protein-1 APAF1 apoptotic protease activating factor 1 APL acute promyelocytic leukemia ARE Antioxidant Response Element Arp actin-related protein ASK1 apoptosis signal-regulating kinase 1 a-syn alpha synuclein ATG autophagy-related ATO Arsenic trioxide ATRA all-trans retinoic acid BAD Bcl-xL/Bcl-2asociated death promoter BAK Bcl-2 antagonist/killer Bax Bcl-2 associated X protein Bcl-2 B-cell lymphoma-2 BID BH3 interacting domain death agonist BIM Bcl-2 interacting mediator of cell death BSO buthionine sulfoximine CA19-9 carbohydrate antigen 19-9 CAC colitis-associated cancer CCI controlled cortical impact CD4 Cluster of differentiation 4 CEA carcinoembryonic antigen CGPC Cys-Gly-Pro-Cys CHK1i checkpoint kinase 1 inhibitors cIAPs cellular inhibitor of apoptosis proteins CKD chronic kidney disease CTCL cutaneous T-cell lymphoma CVDs cardiovascular diseases CXCR4 C -X-C chemokine receptor type 4 DIABLO Diablo IAP-binding mitochondrial protein DLBCL Diffuse large B-cell lymphoma DMF Dimethyl fumarate DR diabetic retinopathy dNTPs deoxyribonucleotides EMT epithelial-mesenchymal transition eNOS endothelial NO synthase ER endoplasmic reticulum FAD flavin adenine dinucleotide FINs ferroptosis inducers 5-FU 5-fluorouracil G1 gap phase GBM glioblastoma multiforme GSDM gasdermin GSDMD gasdermin D GPxs glutathione peroxidases GPX4 glutathione peroxidase 4 GR glutathione reductase Grx glutaredoxin GSH glutathione GSSeSG selenodiglutathione GSSG oxidized glutathione GZM granzyme HCC hepatocellular carcinoma HCV hepatitis C virus HDAC histone deacetylase Hdy-7 isowalsuranolide HIF-1α hypoxia-inducible factor α HIV human immunodeficiency viruses 4-HNE 4-hydroxynonenal H 2 O 2 hydrogen peroxide HREs hypoxia response elements IAPs inhibitor of apoptotic proteins IDET Isodeoxyelephantopin IKK IκB kinase IL-1 interleukin Keap1 Kelch-like ECH-associated protein 1 LDL low-density lipoprotein LTR long terminal repeat LUAD lung adenocarcinoma MCL-1 myeloid cell leukemia-1 MDA malonaldehyde MDS myelodysplastic syndrome MGUS Monoclonal Gammopathy of Undetermined Significance MLKL mixed lineage kinase domain-like protein MPT mitochondrial permeability transition MPP + 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium MS multiple sclerosis Msrs methionine sulfoxide reductases mtDNA mitochondrial DNA NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis NF-κB nuclear factor kappa B NLRP1 NOD-like receptor family pyrin domain-containing 1 NO Nitric Oxide NOXA NADPH oxidase activator Nrf2 nuclear factor-erythroid 2 related factor 2 NSCLC non-small cell lung cancer O 2 - superoxide anions OMV outer membrane vesicle p-Akt phosphorylated-Akt PCD programmed cell death PD Parkinson's disease p-JNK phosphorylated-JNK PLOOH PL-hydroperoxide Prxs peroxiredoxins PTEN phosphatase and tensin homolog PTMs post-translational modifications PTP1B protein tyrosine phosphatase 1B PUMA p53 upregulated modulator of apoptosis RA rheumatoid arthritis Rac-1 Ras-related C3 botulinum toxin substrate 1 Ref-1 redox factor-1 RIPK3 receptor-interacting protein kinase 3 RNR ribonucleotide reductase RNS reactive nitrogen species ROS reactive oxygen species RPE retinal pigment epithelial RRM1 ribonucleotide reductase subunit M1 RS replication stress RT radiotherapy RWE real-world evidence Se selenium SecTRAPs selenium-compromised thioredoxin reductase-derived apoptotic proteins SLC3A2 solute carrier family 3 member 2 SLC7A11 solute carrier family 7 member 11 SMAC Second mitochondria-derived activator of caspases SOD superoxide dismutase STAT3 signal transducer and activator of transcription 3 system Xc − cystine/glutamate antiporter system T-ALL T cell acute lymphoblastic leukemia TAZ PDZ-binding motif TBI traumatic brain injury T2D Type 2 diabetes TIMPs metalloproteinases TNBC Triple negative breast cancer TNF tumor necrosis factor TRAIL TNF-related apoptosis-inducing ligand Trx thioredoxin TrxR thioredoxin reductase TMZ temozolomide Txnip Thioredoxin interacting protein TXNRD1 thioredoxin reductase 1 VEGF vascular endothelial growth factor WRC WAVE regulatory complex

Data availability

No data was used for the research described in the article.

Acknowledgments

Not applicable.