Decoding the molecular mechanisms of pyroptosis and its therapeutic development prospects.

Introduction

Pyroptosis, a form of programmed inflammatory cell death, has emerged as a distinct and critical mode of regulated cell death characterized by the formation of plasma membrane pores, cell swelling, lysis, and the release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Unlike apoptosis, which is generally non-inflammatory and immunologically silent, pyroptosis actively promotes inflammation and immune responses, distinguishing it from other cell death modalities including necrosis and necroptosis ( Sollberger, 2022 ; Burdette et al., 2021 ). The execution of pyroptosis is primarily mediated by the gasdermin (GSDM) family of pore-forming proteins, with gasdermin D (GSDMD) being the most extensively studied member. Upon cleavage by inflammatory caspases such as caspase-1, -4, -5, and -11, the N-terminal domain of GSDMD translocates to the plasma membrane, oligomerizes, and forms large pores, leading to cell membrane rupture and the release of intracellular inflammatory mediators ( Liu and Lieberman, 2024 ; Li and Guo, 2025 ). This process is tightly regulated by inflammasomes, multi-protein complexes that sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), initiating caspase activation and subsequent pyroptosis ( Li et al., 2025a ).

Recent advances have expanded the understanding of pyroptosis beyond canonical inflammasome-dependent pathways to include non-canonical and caspase-3/8-mediated mechanisms, as well as inflammasome-independent activation of GSDMs ( Burdette et al., 2021 ; Liu and Lieberman, 2024 ). The complexity of pyroptotic signaling is further underscored by the involvement of post-translational modifications such as phosphorylation, ubiquitination, and acetylation, which modulate GSDM activity and pyroptosis execution ( Oladapo et al., 2024 ; Chen Y. et al., 2024 ; Li Y. et al., 2022 ). Furthermore, non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been identified as critical regulators of pyroptosis-related gene expression, influencing disease pathogenesis and therapeutic responses ( Wu and Ji, 2026 ; Stoess et al., 2023 ).

Pyroptosis plays a pivotal role in diverse physiological and pathological contexts, including host defense against microbial infections, inflammatory diseases, and cancer. In infectious diseases, pyroptosis contributes to the elimination of intracellular pathogens by destroying their replicative niches and promoting robust inflammatory responses ( Wang Z. et al., 2022 ; Booty and Bryant, 2022 ). However, dysregulated pyroptosis can exacerbate tissue damage and chronic inflammation, contributing to the pathogenesis of autoimmune disorders, metabolic diseases, and neurodegenerative conditions ( Chai R. et al., 2023 ; Feng et al., 2022 ; Huang et al., 2022a ). For example, in diabetic nephropathy (DN) and diabetic cardiomyopathy, pyroptosis induced by hyperglycemia and inflammasome activation leads to renal and cardiac injury, respectively ( Al Mamun et al., 2021a ; Cai Z. et al., 2022 ). Similarly, in neurological diseases such as Alzheimer’s disease and stroke, pyroptosis-mediated neuroinflammation exacerbates neuronal loss and disease progression ( Huang et al., 2022a ; Yang et al., 2021 ).

In the realm of oncology, pyroptosis exhibits a dualistic role. On one hand, pyroptotic cell death can suppress tumor growth by inducing immunogenic cell death, enhancing dendritic cell (DC) maturation, and promoting cytotoxic T lymphocyte infiltration, thereby potentiating antitumor immunity ( Yang F. et al., 2022 ; Johnson and Cui, 2025 ; Hou et al., 2023 ). On the other hand, chronic pyroptosis-driven inflammation can foster a tumor-promoting microenvironment that facilitates cancer progression and metastasis ( Wang L. et al., 2021 ; Yin H. et al., 2024 ). The GSDM family proteins, particularly GSDMD and gasdermin E (GSDME), have been implicated in mediating pyroptosis in various cancers, including lung, breast, ovarian, melanoma, and gastrointestinal tumors ( Hou et al., 2023 ; Huang et al., 2022b ; Wu J. et al., 2022 ; Wu X. et al., 2022 ). Therapeutic strategies aimed at inducing pyroptosis in tumor cells have shown promise in overcoming resistance to conventional therapies and enhancing the efficacy of immunotherapies such as immune checkpoint inhibitors (ICIs) ( Hsu et al., 2021 ; Bao et al., 2024 ; Xie et al., 2025 ).

Technological advances in nanomedicine have opened new avenues for the precise modulation of pyroptosis to achieve therapeutic benefits. Nanoparticle-based delivery systems have been engineered to induce pyroptosis selectively within tumors, thereby amplifying antitumor immune responses while minimizing systemic toxicity ( Ji et al., 2024 ; Qi et al., 2025 ; Trois et al., 2025 ). These nanoplatforms can co-deliver pyroptosis inducers and immunomodulators, facilitating combinatorial therapies that remodel the tumor immune microenvironment (TIME) and improve clinical outcomes ( Huang et al., 2023 ; Yu et al., 2025 ). Moreover, nanomaterials have been employed to inhibit pyroptosis in inflammatory diseases, offering novel therapeutic strategies for conditions such as rheumatoid arthritis (RA), atherosclerosis, and acute pancreatitis ( Wu and Ji, 2026 ; Chai Q. et al., 2023 ; Wu S. et al., 2025 ).

The expanding knowledge of pyroptosis molecular mechanisms has also identified novel therapeutic targets, including inflammasome components, caspases, and GSDMs themselves. Small molecule inhibitors, natural compounds, and biologics targeting these molecules have demonstrated efficacy in preclinical models of inflammatory and metabolic diseases, as well as cancer ( Xu L. et al., 2025 ; Cai et al., 2024 ; Zhang X. et al., 2025 ). For instance, inhibitors of NLRP3 inflammasome activation and GSDMD pore formation have shown promise in mitigating DN, myocardial ischemia-reperfusion injury, and other pathological conditions ( Al Mamun et al., 2021b ; Liu Y. et al., 2024 ; Phungphong et al., 2025 ). Furthermore, modulation of pyroptosis by post-translational modifications and ncRNAs offers additional layers of therapeutic intervention ( Chen Y. et al., 2024 ; Wu and Ji, 2026 ).

In summary, pyroptosis represents a unique and versatile form of programmed cell death with significant implications in health and disease. Its intricate molecular regulation, involvement in diverse pathologies, and the potential for therapeutic modulation underscore its importance as a frontier in biomedical research. This review aims to provide a comprehensive and systematic overview of the molecular mechanisms underlying pyroptosis, its complex roles in various diseases including cancer, cardiovascular, metabolic, neurological, and inflammatory disorders, and the current advances in leveraging pyroptosis pathways for therapeutic development. By integrating recent discoveries and emerging technologies such as nanomedicine and RNA-based therapeutics, this work seeks to inform future research directions and clinical translation efforts targeting pyroptosis.

Pyroptosis: molecular mechanisms, disease relevance, and therapeutic applications

Overview of the molecular mechanisms of pyroptosis

Definition and biological characteristics of pyroptosis

Pyroptosis is a distinct form of inflammatory programmed cell death characterized by cell swelling, plasma membrane rupture, and the release of pro-inflammatory mediators. Unlike apoptosis, which is generally immunologically silent, pyroptosis actively initiates inflammatory responses and serves as an important component of innate immune defense ( Sollberger, 2022 ; Yang F. et al., 2022 ; Al Mamun et al., 2021b ). While this process contributes to pathogen clearance and tissue protection, excessive or dysregulated pyroptosis may promote chronic inflammation and tissue injury ( Liu and Lieberman, 2024 ). Morphologically, pyroptosis is distinguished by rapid cellular swelling and membrane rupture, whereas apoptosis is characterized by cellular shrinkage and preservation of membrane integrity ( Zhang L. et al., 2021 ; Yu et al., 2021 ).

Pyroptosis differs mechanistically from necrosis, which is traditionally viewed as an unregulated form of cell death resulting from acute injury, lacking the specific molecular pathways that characterize pyroptosis. While necrosis also leads to cell swelling and membrane rupture, pyroptosis is a regulated process involving specific signaling cascades and proteolytic events ( Bertheloot et al., 2021 ). Importantly, pyroptosis can be triggered via canonical and non-canonical pathways: the canonical pathway involves caspase-1 activation through inflammasomes, whereas the non-canonical pathway involves caspase-4/5/11 responding to intracellular lipopolysaccharide (LPS) ( Burdette et al., 2021 ). Additionally, caspase-3 and caspase-8 have been implicated in pyroptosis through cleavage of GSDME and GSDMD, respectively, highlighting the complexity and crosstalk between pyroptosis and other cell death modalities such as apoptosis ( Wang et al., 2020 ; Shi et al., 2023 ).

Biologically, pyroptosis serves as a critical innate immune mechanism, eliminating infected or damaged cells and alerting the immune system through the release of inflammatory mediators. This process is essential in controlling infections and shaping the tumor microenvironment (TME), where pyroptosis can have dual roles, either suppressing tumor growth by killing cancer cells or promoting tumor progression through chronic inflammation ( Al Mamun et al., 2021a ; Ning et al., 2022 ; Zhou et al., 2022a ; Wei et al., 2025 ). The inflammatory nature of pyroptosis distinguishes it from apoptosis and necrosis and underscores its significance in various diseases, including infections, autoimmune disorders, cardiovascular diseases, and cancers ( Johnson and Cui, 2025 ; Wang et al., 2020 ; Sordi et al., 2021 ).

Core roles of the GSDM family in pyroptosis

GSDM family proteins, notably GSDMD and GSDME, serve as the pivotal executioners of pyroptosis, a highly inflammatory form of programmed cell death. Structurally, GSDMs share a conserved architecture composed of an N-terminal domain responsible for pore formation and a C-terminal domain that autoinhibits the pore-forming activity in the resting state. Activation of GSDMs is tightly regulated by proteolytic cleavage, which separates the N-terminal domain from the inhibitory C-terminal domain, unleashing the pore-forming capacity essential for pyroptotic cell death. This cleavage liberates the GSDMD N-terminal fragment (GSDMD-N), which oligomerizes and inserts into the plasma membrane to form transmembrane pores. Proteolytic cleavage releases the N-terminal fragment, enabling membrane pore formation and subsequent pyroptotic cell death ( Jiang et al., 2020 ).

The molecular mechanism underlying GSDM pore formation involves the N-terminal domain binding to specific phospholipids on the inner leaflet of the plasma membrane, followed by oligomerization into large, ring-shaped pores approximately 10–20 nm in diameter. These pores compromise membrane integrity, leading to cell swelling, membrane rupture, and the release of intracellular inflammatory mediators. The pore formation is a multistep process beginning with membrane targeting, followed by insertion and oligomerization, which collectively disrupt the lipid bilayer architecture ( Shao, 2021 ; Huston et al., 2023 ). Notably, the pore-forming activity of GSDMs is not only a terminal event leading to cell death but can also be reversible under certain conditions, allowing cells to modulate inflammatory responses without immediate lysis ( Zhao et al., 2025 ). Additionally, post-translational modifications, such as succination of GSDMD by fumarate, can inhibit its cleavage and pore formation, highlighting an additional layer of regulation that controls pyroptotic activity and inflammatory outcomes ( Humphries et al., 2020 ).

Collectively, the GSDM family constitutes a versatile and evolutionarily conserved system for executing pyroptosis through structurally and mechanistically defined pore formation, which is central to inflammatory responses and holds significant therapeutic potential in inflammatory diseases and cancer ( Bai et al., 2025 ; Ouyang et al., 2023 ).

Activation of inflammasomes and pyroptosis signaling

Inflammasomes are cytosolic multiprotein complexes that serve as critical innate immune sensors detecting PAMPs and DAMPs. Among the various inflammasomes, NLRP3 and AIM2 (absent in melanoma 2) are well-characterized for their roles in initiating pyroptosis, a form of inflammatory programmed cell death. The assembly of inflammasomes typically begins with the recognition of activating stimuli by sensor proteins such as NLRP3 or AIM2. Upon activation, these sensors oligomerize and recruit the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which facilitates the recruitment and activation of pro-caspase-1. This leads to the formation of a multiprotein inflammasome complex that acts as a platform for caspase-1 activation. Activated caspase-1 then cleaves pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18 into their mature forms and also cleaves GSDMD, releasing its GSDMD-N that forms pores in the plasma membrane, thereby executing pyroptosis and enabling cytokine release ( Li and Jiang, 2023 ; Liang et al., 2020 ). The NLRP3 inflammasome is unique in its ability to respond to a broad spectrum of stimuli, including microbial infections, metabolic stress, and crystalline substances. Its activation involves complex regulatory mechanisms such as mitochondrial reactive oxygen species (mtROS) generation, potassium efflux, and lysosomal damage, which converge to induce conformational changes that promote inflammasome assembly ( Duan et al., 2020 ; Qiu et al., 2022 ). AIM2, on the other hand, senses cytosolic double-stranded DNA and assembles inflammasomes that similarly activate caspase-1. Recent studies employing optogenetic tools have demonstrated that inflammasome activation leads to distinct phases of cell swelling and membrane rupture during pyroptosis, underscoring the dynamic nature of inflammasome-mediated cell death ( Nadjar et al., 2024 ). Furthermore, novel regulatory proteins such as RACK1 and CANE have been identified to modulate NLRP3 inflammasome assembly and activity, highlighting the complexity of inflammasome regulation ( Duan et al., 2020 ; Kaneko et al., 2024 ). Overall, the assembly and activation of inflammasomes like NLRP3 and AIM2 constitute a tightly regulated process that integrates diverse cellular signals to initiate pyroptosis and pro-inflammatory cytokine release, essential for host defense and homeostasis.

The canonical and non-canonical inflammasome pathways represent two distinct but interconnected signaling cascades that culminate in pyroptosis and inflammatory cytokine release. The canonical pathway is initiated by inflammasome sensors such as NLRP3, AIM2, or NLRC4, which recruit and activate caspase-1 through the adaptor ASC. Activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to their mature forms and processes GSDMD, whose GSDMD-N forms membrane pores leading to pyroptotic cell death ( Li and Jiang, 2023 ; Liang et al., 2020 ). In contrast, the non-canonical pathway involves direct sensing of cytosolic LPS by inflammatory caspases caspase-4 and caspase-5 in humans, and caspase-11 in mice. These caspases do not require upstream inflammasome sensors for activation; instead, they directly bind LPS, undergo autoproteolysis, and cleave GSDMD to induce pyroptosis ( Wright et al., 2022 ; Wu J. et al., 2023 ). Notably, non-canonical inflammasome activation can also promote secondary activation of the canonical NLRP3 inflammasome, linking the two pathways functionally ( Wu J. et al., 2023 ). While both pathways converge on GSDMD cleavage and pore formation, they differ in their upstream sensing mechanisms and caspase utilization. The canonical pathway is more versatile, responding to a wide range of stimuli via various sensors, whereas the non-canonical pathway specifically detects intracellular LPS, playing a critical role in defense against gram-negative bacterial infections and in sepsis pathogenesis ( Wright et al., 2022 ; Oh et al., 2025 ). Furthermore, zinc homeostasis has been shown to regulate both canonical and non-canonical inflammasome activation by inhibiting caspase-1 and caspase-4/5/11 activities, indicating additional layers of regulation ( Gong X. et al., 2024 ). Importantly, cell type-specific differences exist; for example, neutrophils can resist pyroptotic lysis despite inflammasome activation, allowing them to release IL-1β while maintaining viability, highlighting nuanced regulation of pyroptosis ( Dubyak et al., 2023 ). Therapeutically, targeting either pathway holds promise for treating inflammatory diseases, sepsis, and cancer, with ongoing research exploring inhibitors that can broadly suppress inflammasome activation ( Anderson et al., 2024 ; Seo et al., 2025 ). In summary, the canonical and non-canonical inflammasome pathways represent complementary arms of innate immunity, distinguished by their caspase usage and activation mechanisms, yet interconnected through shared downstream effectors and biological outcomes.

Other regulatory mechanisms: caspase-3/8 and granzyme-mediated pathways

Apoptotic caspases, particularly caspase-3 and caspase-8, have emerged as critical regulators intersecting with pyroptotic pathways, revealing a complex crosstalk between apoptosis and pyroptosis. Traditionally, pyroptosis was primarily associated with inflammatory caspases such as caspase-1, -4, -5, and -11, which cleave GSDMD to form membrane pores. However, recent studies have demonstrated that caspase-3 and caspase-8, key executors of apoptosis, can also induce pyroptosis through cleavage of distinct GSDM family members, especially GSDME and GSDMD, respectively. For instance, caspase-3 cleaves GSDME, liberating its N-terminal domain that forms membrane pores, thereby converting apoptotic signals into pyroptotic cell death characterized by cell swelling and inflammatory cytokine release ( Liu M. et al., 2025 ; Zheng et al., 2021 ). This mechanism has been implicated in diverse pathological contexts, including neurodegenerative diseases such as Alzheimer’s disease, where elevated caspase-8 expression activates caspase-3 and triggers GSDME-dependent pyroptosis, exacerbating neuroinflammation and cell death ( Liu M. et al., 2025 ). Similarly, caspase-8 can directly cleave GSDMD, inducing pyroptosis independently of caspase-1, as observed in macrophages infected with pathogens like Yersinia or stimulated with LPS and TAK1 inhibitors ( Zheng et al., 2021 ; Ma et al., 2025 ). Moreover, caspase-8 activation is not limited to pathogen responses but also plays a role in sterile inflammation and cancer. For example, α-ketoglutarate induces pyroptosis via caspase-8-mediated cleavage of GSDMC in tumor cells, linking metabolic cues to inflammatory cell death and tumor suppression ( Zhang J. Y. et al., 2021 ). The interplay between caspase-8 and caspase-3 is further highlighted during influenza A virus infection, where caspase-8 autoprocessing activates caspase-3 to suppress GSDMD-mediated pyroptosis, balancing cell death modalities to modulate inflammation and host defense ( Wang Y. et al., 2021 ). This crosstalk underscores the dual role of caspase-3 and caspase-8 as molecular switches that can direct cells towards apoptosis or pyroptosis depending on cellular context and stimuli, thereby fine-tuning inflammatory responses. Additionally, caspase-8’s involvement in inflammasome-associated cell death pathways suggests it can mediate apoptosis, pyroptosis, or necroptosis, contributing to a broader regulated cell death network termed PANoptosis ( Song K. et al., 2025 ; Tsuchiya, 2020 ). Therapeutically, targeting caspase-3/8-mediated pyroptosis pathways offers promising avenues for diseases characterized by excessive inflammation or defective cell death, including cancer, neurodegeneration, and infectious diseases. For example, inhibition of caspase-8 attenuates pyroptosis and inflammation in bronchopulmonary dysplasia models, improving alveolar development and vascular remodeling ( Huang et al., 2025 ). In summary, apoptotic caspases caspase-3 and caspase-8 serve as pivotal regulators bridging apoptosis and pyroptosis, orchestrating cell fate decisions through GSDM cleavage and providing novel targets for modulating inflammatory cell death in various diseases.

Granzyme B (GzmB), a serine protease secreted by cytotoxic lymphocytes such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), has been identified as a potent inducer of pyroptosis through direct cleavage of GSDM family proteins, thereby linking immune effector functions to inflammatory cell death. Traditionally recognized for its role in inducing apoptosis via caspase activation within target cells, GzmB has recently been shown to cleave GSDME, triggering pyroptosis characterized by membrane pore formation, cell swelling, and release of proinflammatory cytokines ( Tan et al., 2025 ; Wang M. et al., 2026 ). This GzmB -mediated pyroptotic pathway enhances immune-mediated tumor clearance by converting target cancer cells into proinflammatory entities that recruit and activate additional immune cells. For instance, a novel immunotoxin combining an HPV16 E7-specific affibody with GzmB (ZHPV16E7-GrB) induces pyroptosis in HPV16-positive cervical cancer cells by directly cleaving GSDME, independent of caspase-3 activation, resulting in membrane rupture and release of inflammatory cytokines that potentiate antitumor immunity ( Tan et al., 2025 ). Furthermore, GzmB expression is upregulated in pathological conditions such as renal fibrosis, where its knockdown reduces pyroptosis and fibrosis by inhibiting NLRP3 inflammasome activation and downstream JAK2/STAT3 signaling, highlighting its role beyond cytotoxicity in modulating inflammatory responses ( Wang M. et al., 2026 ). The GzmB-GSDME axis also contributes to the immune microenvironment remodeling in cancers such as triple-negative breast cancer (TNBC), where pyroptosis induction enhances CD8 + T cell infiltration and GzmB presence, amplifying antitumor immunity ( Yang et al., 2024 ). The GzmB-mediated pyroptosis pathway represents a critical intersection between immune cytotoxicity and inflammatory cell death, offering therapeutic potential for enhancing antitumor immunity and controlling inflammatory diseases. Targeting this pathway could improve immunotherapy efficacy by promoting immunogenic cell death and overcoming tumor immune evasion. In conclusion, GzmB acts as a key mediator of pyroptosis in immune surveillance and pathology, expanding the functional repertoire of cytotoxic lymphocytes in host defense and disease modulation.

NcRNAs and epigenetic regulation

LncRNAs and circular RNAs (circRNAs) have emerged as critical regulators of pyroptosis by modulating the expression of genes involved in this inflammatory form of programmed cell death. LncRNAs, typically over 200 nucleotides in length and lacking protein-coding capacity, exert diverse molecular functions including acting as molecular sponges for miRNAs, scaffolding epigenetic modifiers, and guiding chromatin remodeling complexes to specific genomic loci. For instance, in cancer contexts such as HCC and colorectal cancer (CRC), lncRNAs have been shown to influence pyroptosis by regulating the expression of inflammasome components and GSDMs, thereby affecting tumor cell proliferation, invasion, and treatment resistance ( Luo et al., 2026 ; Taha et al., 2025 ). Similarly, circRNAs, characterized by covalently closed loop structures, regulate pyroptosis-related genes primarily through competing endogenous RNA (ceRNA) networks, sequestering miRNAs that target pyroptosis mediators, thus fine-tuning the pyroptotic response. In cardiovascular diseases and pulmonary arterial hypertension, ncRNAs including lncRNAs and circRNAs modulate pyroptosis pathways by influencing inflammatory signaling and cell death in vascular cells, which contributes to disease progression ( Jiang et al., 2023 ; Chen C. et al., 2024 ). Moreover, in immune-mediated diseases such as vasculitis, lncRNAs and circRNAs packaged in extracellular vesicles can regulate pyroptosis and inflammation in target cells, highlighting their role in intercellular communication and immune regulation ( Tang et al., 2024 ). The regulatory capacity of these ncRNAs extends to controlling transcription factors and signaling pathways that govern inflammasome activation, caspase cleavage, and GSDM pore formation, all central to pyroptosis execution. Given their tissue-specific expression and multifaceted regulatory roles, lncRNAs and circRNAs represent promising therapeutic targets and biomarkers for diseases where pyroptosis plays a pathogenic or protective role. Advances in delivery technologies, such as lentiviral vectors and lipid nanoparticles, are facilitating the development of lncRNA-based therapies aimed at modulating pyroptosis for improved clinical outcomes ( Fu et al., 2026 ). Collectively, the intricate regulation of pyroptosis by lncRNAs and circRNAs underscores the complexity of epigenetic control in inflammatory cell death and offers novel avenues for targeted intervention.

Epigenetic modifications such as DNA methylation and post-translational modifications including ubiquitination critically influence the expression and functional stability of key proteins involved in pyroptosis, thereby modulating the pyroptotic pathway and its biological consequences. DNA methylation, typically involving the addition of methyl groups to cytosine residues in CpG islands, can repress or activate gene transcription depending on the context. Aberrant DNA methylation patterns have been implicated in the dysregulation of inflammasome components such as NLRP3 and caspase-1, which are pivotal for pyroptosis initiation. For example, hypermethylation of promoter regions can silence genes encoding inflammasome sensors or effectors, attenuating pyroptotic responses and influencing disease progression in cancer and inflammatory disorders ( Zhang R. N. et al., 2023 ; Raneros et al., 2021 ). Conversely, hypomethylation may lead to overexpression of pyroptosis-related genes, contributing to excessive inflammation and tissue damage as observed in sepsis and cardiovascular diseases ( Chen C. et al., 2024 ; Wen et al., 2022 ). Ubiquitination, a reversible post-translational modification involving the attachment of ubiquitin molecules to lysine residues on target proteins, regulates the stability, localization, and activity of pyroptosis mediators. Key proteins such as NLRP3 undergo ubiquitination that can either mark them for proteasomal degradation or modulate their inflammasome assembly capacity. Deubiquitinases and E3 ubiquitin ligases dynamically control this balance, thereby fine-tuning inflammasome activation and downstream pyroptotic events ( He et al., 2025 ). The crosstalk between DNA methylation and ubiquitination pathways further adds complexity to pyroptosis regulation; epigenetic states can influence the expression of ubiquitin-modifying enzymes, while ubiquitination can affect chromatin modifiers that control DNA methylation landscapes. This multilayered regulation is evident in aging-related diseases where epigenetic reprogramming recalibrates pyroptosis thresholds, impacting tissue homeostasis and disease susceptibility ( Liu L. et al., 2025 ). Understanding these epigenetic and post-translational mechanisms opens new therapeutic possibilities, such as targeting DNA methyltransferases or ubiquitin-proteasome system components to restore balanced pyroptosis in pathological conditions, including cancer, sepsis, and chronic inflammatory diseases ( Zhang R. N. et al., 2023 ; Zhou et al., 2024 ). Thus, DNA methylation and ubiquitination constitute fundamental regulatory axes that modulate the expression and function of pyroptosis key proteins, shaping the cellular inflammatory response and influencing disease outcomes ( Figure 1 ). The major activation pathways and regulatory layers governing pyroptosis are summarized in Table 1 , highlighting the convergence of diverse upstream signals on GSDM-mediated membrane pore formation.

Schematic overview of the core molecular pathways underlying pyroptosis. Pyroptosis is initiated through canonical inflammasome activation, non-canonical caspase pathways, and apoptosis-associated caspase signaling, all converging on gasdermin (GSDM) cleavage and membrane pore formation. The release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs) amplifies inflammatory responses and links pyroptosis to innate immunity and disease pathogenesis.

The role of pyroptosis in tumor occurrence and development

Effects of pyroptosis on tumor cell growth and apoptosis

Pyroptosis, a form of programmed inflammatory cell death mediated primarily by the GSDM family, has emerged as a critical regulator of tumor cell fate, influencing both tumor growth inhibition and the TME. The molecular mechanism underlying pyroptosis-induced tumor cell death typically involves activation of inflammasomes, leading to caspase cleavage (notably caspase-1, caspase-3, caspase-8, and caspase-9) and subsequent cleavage of GSDM proteins such as GSDMD and GSDME. The GSDMD-Ns of these GSDMs oligomerize to form pores in the plasma membrane, causing cell swelling, membrane rupture, and release of pro-inflammatory cytokines like IL-1β and IL-18, which further amplify anti-tumor immune responses ( Ju et al., 2021 ; Wen et al., 2023 ; Tan et al., 2021 ). Various studies have demonstrated that inducing pyroptosis in tumor cells leads to inhibition of tumor proliferation, migration, and invasion across multiple cancer types including esophageal cancer, lung cancer, hepatocellular carcinoma (HCC), and anaplastic thyroid carcinoma. For instance, inhibition of endogenous hydrogen sulfide in esophageal cancer cells promoted pyroptosis via reactive oxygen species (ROS)-mediated NF-κB signaling, resulting in suppressed tumor growth both in vitro and in vivo ( Wang H. G. et al., 2023 ). Similarly, natural compounds such as isoquercitrin and osthole have been shown to induce pyroptosis through activation of the NLRP3 inflammasome and caspase-3/GSDME pathways, respectively, thereby inhibiting lung cancer and cervical cancer cell growth ( Fan et al., 2025 ; Wang J. et al., 2022 ). Phototherapy approaches using mitochondria-targeted cyanine dyes or carbon dot photosensitizers have also been optimized to trigger pyroptosis alongside apoptosis, enhancing antitumor efficacy and immune activation ( Zhao X. et al., 2024 ; Chen T. et al., 2024 ). Mechanistically, pyroptosis not only directly kills tumor cells but also remodels the TIME by recruiting and activating DCs and CTLs, converting immunologically “cold” tumors into “hot” tumors that are more susceptible to immunotherapy ( Inkol et al., 2024 ; Li M. et al., 2023 ). Furthermore, pyroptosis induction has been linked to overcoming apoptosis resistance, a common hurdle in cancer therapy, by providing an alternative cell death pathway that amplifies treatment-induced tumor cell killing ( Li M. et al., 2023 ; Zhou et al., 2025 ). However, tumor cells have evolved sophisticated strategies to evade pyroptosis, which limits its therapeutic potential. One such mechanism involves the overexpression of Sorcin in HCC, which interacts with the NLRP3 inflammasome to inhibit pyroptosis, thereby promoting tumor proliferation and metastasis ( Li Z. et al., 2023 ). Another example is the elevated expression of Niemann-Pick C1 (NPC1) in various cancers, which maintains cholesterol homeostasis to protect tumor cells from pyroptosis, and its inhibition sensitizes tumors to pyroptotic cell death ( Zhang C. et al., 2025 ). Additionally, tumor cells may downregulate GSDM expression or interfere with caspase activation to suppress pyroptosis execution ( Wang Y. et al., 2024 ; Ren Y. et al., 2023 ). Collectively, these findings underscore the dual role of pyroptosis in tumor biology: as a potent tumor suppressor mechanism through direct tumor cell killing and immune activation, and as a process that can be subverted by tumors to facilitate survival. Harnessing pyroptosis for cancer therapy thus requires a nuanced understanding of these molecular mechanisms to effectively induce pyroptosis in tumor cells while overcoming their evasion strategies.

Interaction between pyroptosis and TIME

Pyroptosis serves as a critical mechanism in converting immunologically “cold” tumors, characterized by low immune cell infiltration and poor responsiveness to immunotherapy, into “hot” tumors with robust immune activation. This transformation is essential for improving the efficacy of immune checkpoint blockade (ICB) therapies, which rely on pre-existing antitumor immune responses. Pyroptosis-induced inflammation promotes the release of tumor-associated antigens (TAAs) and DAMPs, thereby enhancing DC maturation and T cell priming, which collectively increase tumor immunogenicity ( Wang W. et al., 2022 ; Yang Y. et al., 2023 ). Experimental models have demonstrated that pyroptosis induction sensitizes tumors to anti-PD-1 therapy by increasing CD8 + T cell infiltration and reducing immunosuppressive cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) ( Wu J. et al., 2022 ; Wu F. et al., 2023 ). Nanoparticle-based delivery systems and small molecule agents that trigger pyroptosis have been developed to exploit this mechanism, successfully remodeling the TIME and enhancing immunotherapy responses in otherwise refractory tumors ( Chen et al., 2024a ; Liu et al., 2026a ; Liu et al., 2026b ).

Furthermore, pyroptosis influences the polarization and function of tumor-associated macrophages (TAMs), shifting them toward a pro-inflammatory M1 phenotype that supports antitumor immunity, while suppressing the immunosuppressive M2 phenotype ( Huang X. et al., 2022 ; Ji et al., 2023 ). Dietary polyphenols and epigenetic modulators have been reported to induce pyroptosis and modulate TAM polarization, thereby reshaping the TIME to favor immune activation ( Huang X. et al., 2022 ). In addition, pyroptosis-related gene signatures correlate with immune cell infiltration patterns, immune checkpoint expression, and patient prognosis across multiple cancer types, underscoring the integral role of pyroptosis in tumor-immune interactions ( Li L. et al., 2024 ; Chen et al., 2021 ).

The pro-inflammatory environment generated by pyroptosis also modulates immune checkpoint expression, with observed upregulation of PD-L1 and other checkpoint molecules in response to pyroptosis-related signaling, suggesting a complex interplay between pyroptosis and immune evasion mechanisms ( Zhang Y. et al., 2025 ; Yin Q. et al., 2024 ). Nonetheless, the net effect of pyroptosis-induced inflammation is the enhancement of tumor immunogenicity and promotion of effective antitumor immune responses, particularly when combined with ICB therapies ( Wang W. et al., 2022 ).

One of the major challenges in cancer immunotherapy is the presence of “cold tumors,” which are characterized by low immune cell infiltration, minimal antigen presentation, and poor responsiveness to ICIs. Pyroptosis has emerged as a key mechanism capable of converting these immunologically inert tumors into “hot tumors” with active immune microenvironments ( Li M. et al., 2023 ; Wang W. et al., 2022 ). The inflammatory nature of pyroptosis facilitates the release of TAAs, DAMPs, and pro-inflammatory cytokines, which collectively enhance DC activation and T cell priming, essential steps for effective antitumor immunity ( Yang Y. et al., 2023 ; Zhou et al., 2022b ).

Experimental studies have demonstrated that induction of pyroptosis via chemotherapeutic agents, nanomedicine, or genetic modulation increases infiltration of CD8 + T cells and NK cells into tumor sites, thereby enhancing immune surveillance and tumor cell killing ( Yang et al., 2024 ; Li F. et al., 2023 ). For example, pyroptosis induction by histone deacetylase inhibitors in triple-negative breast cancer models resulted in increased CD8 + lymphocyte infiltration and GzmB expression, correlating with tumor growth inhibition ( Yang et al., 2024 ). Similarly, vesicular stomatitis virus (VSV)-mediated pyroptosis sensitized immunologically cold tumors to checkpoint blockade by recruiting cytotoxic lymphocytes ( Lin et al., 2022 ).

Moreover, pyroptosis modulates the TME by reducing immunosuppressive cell populations such as MDSCs and Tregs, and promoting the polarization of TAMs toward the M1 phenotype, which supports antitumor immunity ( Wu F. et al., 2023 ; Ji et al., 2023 ). This remodeling of the immune landscape is critical for overcoming immune evasion and resistance to ICIs. Nanoparticle-based pyroptosis inducers have been engineered to specifically target tumor cells, inducing localized pyroptosis and enhancing immune cell infiltration without systemic toxicity ( Chen et al., 2024a ; Zhao L. et al., 2024 ).

Clinical and bioinformatic analyses further support the prognostic significance of pyroptosis-related gene signatures in predicting immune infiltration and response to immunotherapy across various cancers, including bladder cancer, gastric cancer, and gliomas ( Chen et al., 2021 ; Zhou et al., 2022b ; Cai Y. et al., 2022 ). These findings underscore the therapeutic potential of pyroptosis induction as a strategy to convert cold tumors into hot tumors, thereby improving the efficacy of immunotherapies.

Heterogeneous roles of pyroptosis in different tumor types

Pyroptosis is increasingly recognized as a double-edged sword in cancer biology. While it can suppress tumor growth by directly eliminating malignant cells and stimulating antitumor immunity, excessive or persistent pyroptotic signaling may also promote tumor progression through chronic inflammation. This apparent contradiction suggests that the biological consequences of pyroptosis are highly context dependent rather than universally beneficial or detrimental.

On one hand, activation of pyroptosis results in the release of tumor antigens, DAMPs, and pro-inflammatory cytokines such as IL-1β and IL-18, thereby enhancing dendritic cell maturation, cytotoxic T-cell recruitment, and immune checkpoint blockade responsiveness ( Fang et al., 2023 ). Several studies have demonstrated that pyroptosis-associated gene signatures correlate with increased immune infiltration and improved therapeutic outcomes in multiple cancers, supporting its role as an immunogenic form of cell death ( Kuo et al., 2023 ). On the other hand, sustained pyroptotic activity may establish a pro-tumorigenic inflammatory microenvironment. The context-dependent nature of pyroptosis is particularly evident in gliomas ( Sun et al., 2023 ). Multi-omics analyses have identified distinct pyroptosis-associated molecular subgroups with markedly different immune landscapes and clinical outcomes ( Chen M. et al., 2024 ). Interestingly, tumors with high pyroptosis scores often exhibit increased immune infiltration but worse survival, suggesting that immune-cell abundance alone does not necessarily translate into effective antitumor immunity. Instead, the composition and functional state of infiltrating immune cells appear to be critical determinants of outcome ( Zhou et al., 2026 ).

To capture this heterogeneity, several scoring systems, including the Pyroptosis Immune Prognostic Model (PIPM) and PyroScore, have been developed to integrate pyroptosis-related gene expression with immune characteristics ( Shen et al., 2025 ). These models show promising prognostic and predictive value across multiple cancer types. However, most have been established using retrospective transcriptomic datasets and lack prospective clinical validation. Furthermore, substantial variability exists in the biomarkers and algorithms used, limiting their immediate clinical applicability ( Gao et al., 2023 ; Zheng et al., 2022 ).

In summary, the heterogeneous roles of pyroptosis in different tumor types reflect the complex interplay between tumor cells and the immune microenvironment. The development and validation of pyroptosis scoring systems provide valuable tools for clinical application, enabling improved prognostic prediction and personalized therapy, particularly in gliomas. Future research focusing on the molecular mechanisms underlying pyroptosis heterogeneity and its modulation of the TME will be pivotal for translating these insights into effective therapeutic interventions ( Figure 2 ).

Dual roles of pyroptosis in tumor development and antitumor immunity. Pyroptosis can suppress tumor growth by inducing inflammatory tumor cell death and enhancing immune cell recruitment, while persistent or dysregulated pyroptosis may promote tumor progression by sustaining a pro-tumorigenic inflammatory microenvironment. These opposing effects highlight the context-dependent nature of pyroptosis in cancer.

Pyroptosis and inflammatory diseases and autoimmune diseases

The mechanisms of pyroptosis in atherosclerosis

Endothelial cells (ECs) are among the first vascular cells affected by pyroptosis in atherosclerosis. NLRP3 inflammasome activation in ECs induces pyroptotic death, resulting in endothelial dysfunction, increased vascular permeability, and enhanced leukocyte adhesion, thereby promoting lesion initiation ( Liu X. et al., 2023 ; Bai et al., 2021 ). Experimental models have demonstrated that pharmacological inhibition of NLRP3 or downstream effectors such as caspase-1 and GSDMD attenuates endothelial pyroptosis and reduces plaque formation, highlighting the therapeutic potential of targeting this pathway ( Lin et al., 2021 ; Xing et al., 2020 ). Moreover, recent studies elucidate that ncRNAs, including miRNAs and lncRNAs, regulate NLRP3 inflammasome expression and activity in ECs, modulating pyroptosis and vascular inflammation ( Wang Y. P. et al., 2025 ; Khojali et al., 2024 ). For instance, miR-302c-3p directly targets NLRP3 to suppress endothelial pyroptosis, while lncRNA HIF1A-AS2 delivered via endothelial extracellular vesicles promotes pyroptosis by upregulating NLRP3 ( Bai et al., 2021 ; Li P. et al., 2023 ). Additionally, upstream signaling pathways such as NF-κB and thioredoxin-interacting protein (TXNIP) modulate NLRP3 inflammasome priming and activation in ECs, linking oxidative stress and inflammation to pyroptosis ( Hendawy et al., 2025 ; Li J. et al., 2022 ). The involvement of pyroptosis in ECs is further supported by in vivo evidence showing that interventions like pulsed electromagnetic fields and natural compounds (e.g., salidroside) reduce endothelial pyroptosis and ameliorate atherosclerotic lesions by inhibiting NLRP3 inflammasome activation ( Xing et al., 2020 ; Cheng et al., 2025 ). Collectively, these findings underscore that NLRP3 inflammasome-mediated pyroptosis in vascular ECs is a critical mechanism driving endothelial dysfunction and atherosclerosis progression, offering promising targets for therapeutic intervention.

Moreover, pyroptotic ECs release microparticles containing inflammatory mediators, which propagate vascular inflammation and facilitate crosstalk among ECs, macrophages, and smooth muscle cells, accelerating atherogenesis ( Sun et al., 2021 ). The amplification of inflammation by pyroptosis is tightly regulated by multiple signaling pathways, including NF-κB, TXNIP, and JAK/STAT, which modulate inflammasome activation and cytokine production ( Hendawy et al., 2025 ; Li J. et al., 2022 ; Zhou and Song, 2023 ). Therapeutic interventions targeting pyroptosis-related molecules have demonstrated efficacy in reducing inflammatory cytokine release and stabilizing plaques. For instance, bone marrow mesenchymal stem cell-derived exosomes (MSC-Exos) suppress NLRP3/caspase-1/GSDMD-mediated pyroptosis, decreasing IL-1β and IL-18 levels and alleviating atherosclerosis progression ( Bai et al., 2023 ). Beyond MSC-derived exosomes, increasing evidence indicates that extracellular vesicles (EVs) from diverse biological sources also possess significant anti-inflammatory and anti-pyroptotic properties ( Khalilzad et al., 2025a ). Placenta-derived EVs, particularly those isolated from human placental mesenchymal stromal cells and trophoblast-associated tissues, exhibit potent immunomodulatory effects through suppression of NLRP3 inflammasome activation, reduction of pro-inflammatory cytokine production, and promotion of tissue repair ( Ruan et al., 2025 ; Khalilzad et al., 2025b ). Their favorable safety profile and naturally immunosuppressive characteristics make them attractive candidates for inflammatory disease treatment.

Regulatory network of pyroptosis in DN

The regulatory network of pyroptosis in DN is complex and involves multiple molecular players, including ncRNAs, inflammasomes, and signaling pathways that converge to exacerbate renal cell injury and inflammation. Recent studies have highlighted the critical role of ncRNAs, including lncRNAs and circRNAs, in modulating pyroptosis and thereby influencing the progression of DN. For instance, lncRNA MALAT1 is significantly upregulated in DN patients and correlates with increased serum caspase-1 and IL-18 levels, markers of pyroptosis, indicating its involvement in promoting renal tubular epithelial cell injury through pyroptotic mechanisms ( Shoeib et al., 2023 ). Similarly, circ_0004951 promotes pyroptosis in renal tubular epithelial cells by sponging miR-93-5p, which normally suppresses NLRP3 inflammasome activation; thus, circ_0004951 upregulation leads to enhanced NLRP3-mediated pyroptosis and inflammation in DN ( Wang Y. et al., 2022 ). These ncRNAs act as upstream regulators that fine-tune inflammasome activation and pyroptotic cell death, underscoring their potential as biomarkers and therapeutic targets.

Inflammasome inhibitors have garnered attention as potential therapeutic agents in DN. Natural compounds such as puerarin, syringaresinol, and tanshinone IIA have demonstrated efficacy in mitigating pyroptosis by inhibiting caspase-1 activation and NLRP3 inflammasome assembly, thereby reducing inflammatory cytokine release and renal damage ( Chen Q. et al., 2024 ; Li G. et al., 2023 ; Wu Q. et al., 2023 ). Furthermore, hirudin ameliorates DN by suppressing GSDMD-mediated pyroptosis through regulation of interferon regulatory factor 2 (IRF2), highlighting the role of transcriptional regulation in pyroptosis control ( Han et al., 2023 ). The identification of pyroptosis-related genes and their associated pathways has facilitated the screening of numerous candidate drugs that target key nodes in the pyroptosis network, offering a promising avenue for DN treatment ( Yan et al., 2023 ).

The NLRP3 inflammasome is a critical driver of pyroptosis in DN, and its inhibition has emerged as a promising therapeutic strategy to attenuate renal inflammation and fibrosis. Multiple pharmacological agents and natural compounds have demonstrated efficacy in suppressing inflammasome activation and downstream pyroptotic pathways in preclinical models of DN. For example, puerarin administration in streptozotocin-induced diabetic mice reduces fasting blood glucose, alleviates glomerular lesions, and inhibits caspase-1-mediated pyroptosis in podocytes, as evidenced by decreased IL-1β and IL-18 release ( Chen Q. et al., 2024 ). Similarly, syringaresinol exerts renoprotective effects by activating NRF2 signaling, which suppresses NLRP3/caspase-1/GSDMD-mediated pyroptosis and oxidative stress in diabetic mice ( Li G. et al., 2023 ). Tanshinone IIA, derived from Salvia miltiorrhiza, inhibits oxidative stress-induced pyroptosis in glomerular by modulating the TXNIP/NLRP3 inflammasome axis, thereby mitigating renal injury ( Wu Q. et al., 2023 ). These findings highlight the therapeutic potential of targeting upstream oxidative stress and inflammasome activation to prevent pyroptotic cell death.

Other agents such as hirudin inhibit GSDMD-mediated pyroptosis by downregulating interferon regulatory factor 2, resulting in improved renal function and reduced tubular injury in diabetic models ( Han et al., 2023 ). Additionally, the MIF inhibitor Chicago sky blue 6B suppresses NLRP3 inflammasome activation and fibrosis by downregulating the NLRP3/caspase-1/GSDMD/IL-1β pathway in DN ( Chen et al., 2026 ). The identification of pyroptosis-related gene signatures has facilitated the screening of 65 potential therapeutic compounds targeting key pyroptosis mediators, providing a rich resource for drug development ( Yan et al., 2023 ).

Relationship between pyroptosis and autoimmune diseases

Pyroptosis, a highly inflammatory form of programmed cell death mediated by GSDM family proteins, has been increasingly recognized as a pivotal mechanism contributing to the pathogenesis of various autoimmune diseases, including RA, systemic lupus erythematosus (SLE), and multiple sclerosis (MS). In RA, excessive pyroptosis is driven by inflammatory mediators such as tumor necrosis factor (TNF) and activation of the NLRP3 inflammasome, which exacerbate synovial inflammation and joint damage. Fibroblast-like synoviocytes (FLSs) in RA patients demonstrate elevated pyroptotic activity, with increased expression of caspase-1, GSDMD, and pro-inflammatory cytokines IL-1β and IL-18, contributing to chronic synovitis and cartilage degradation ( Song et al., 2024 ; Xin et al., 2024 ; Ren C. et al., 2023 ). Similarly, in SLE, pyroptosis facilitates the release of nuclear antigens and pro-inflammatory cytokines, perpetuating autoantibody production and systemic inflammation. Elevated pyroptosis markers have been detected in immune cells and affected tissues, highlighting its role in disease progression ( Song et al., 2024 ; Yao et al., 2024 ). In MS, pyroptosis of central nervous system cells, including oligodendrocytes, is implicated in demyelination and neuroinflammation. Activation of caspase-11 and the NLRP3 inflammasome promotes pyroptotic cell death, which amplifies immune cell infiltration and tissue injury ( Song et al., 2024 ; Song et al., 2022 ). The overactivation of pyroptosis leads to sustained chronic inflammation and tissue damage, characteristic of autoimmune pathology. Mechanistically, inflammasome activation triggers caspase-1 or caspase-11/4/5 cleavage of GSDMs, forming membrane pores that cause cell lysis and release of inflammatory mediators, thereby disrupting immune homeostasis and promoting autoimmunity ( Burdette et al., 2021 ; Wu et al., 2021a ). Therapeutic strategies targeting pyroptosis pathways, including inhibition of NLRP3 inflammasome, caspases, or GSDM pore formation, have shown promise in preclinical models of autoimmune diseases. For example, nanoliposomes responsive to pyroptotic signals have been developed to deliver anti-pyroptotic drugs selectively to inflamed tissues, effectively reducing autoimmune inflammatory damage in arthritis and inflammatory bowel disease (IBD) models ( Xu et al., 2024 ; Pan et al., 2024 ). Moreover, agents such as dimethyl fumarate and disulfiram have demonstrated the ability to inhibit GSDMD-mediated pyroptosis, thereby alleviating inflammation in autoimmune conditions ( Bandharam et al., 2023 ; Gong W. et al., 2024 ). Collectively, these findings underscore the critical role of pyroptosis in autoimmune disease pathogenesis, where its dysregulation drives chronic inflammation and tissue injury. The excessive activation of pyroptosis not only amplifies inflammatory cascades but also promotes the recruitment and activation of autoreactive immune cells, perpetuating a vicious cycle of immune-mediated damage. Understanding the molecular mechanisms linking pyroptosis to autoimmunity provides valuable insights for developing targeted therapies aimed at modulating pyroptotic pathways to restore immune tolerance and prevent tissue destruction in autoimmune diseases ( Song et al., 2024 ; You et al., 2022 ; Zhang et al., 2021a ). Additionally, environmental exposure has recently emerged as an important upstream regulator of pyroptosis and is increasingly recognized as a contributor to multiple chronic diseases. A growing body of evidence indicates that diverse environmental pollutants—including particulate matter, heavy metals, pesticides, engineered nanoparticles, per- and polyfluoroalkyl substances (PFAS), and microplastics—can activate pyroptotic signaling pathways in various tissues ( Berkel and Cacan, 2023 ).

Role of pyroptosis regulation in chronic intestinal diseases

Pyroptosis is increasingly recognized as an important mechanism in chronic intestinal diseases, particularly inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease ( Zhang et al., 2022a ). In response to microbial infection, intestinal dysbiosis, and endogenous danger signals, the NLRP3 inflammasome activates caspase-1, which subsequently cleaves GSDMD and promotes the release of IL-1β and IL-18 ( Shao et al., 2019 ). This NLRP3–caspase-1–GSDMD axis disrupts intestinal epithelial barrier integrity, amplifies mucosal inflammation, and contributes to persistent immune dysregulation in IBD. Consistently, reviews focused on IBD have summarized that NLRP3 inflammasome activation and pyroptosis are closely associated with intestinal inflammation and disease progression.

The relationship between gut microbiota and pyroptosis further strengthens this pathogenic axis ( Pérez-Rodríguez and Mercanoglu Taban, 2019 ). Dysbiosis may promote excessive inflammasome activation in intestinal epithelial cells and macrophages, whereas microbiota-derived metabolites, particularly short-chain fatty acids such as butyrate, help maintain epithelial homeostasis and regulate intestinal immune responses ( Shao et al., 2019 ; Fingelkurts and Fingelkurts, 2019 ). Therefore, targeting the microbiota–NLRP3–caspase-1–GSDMD pathway, either by inflammasome inhibition or microbiota-modulating strategies, may provide a promising therapeutic direction for IBD and related chronic intestinal inflammatory disorders ( Zhang et al., 2022a ). Therapeutically, inhibition of the NLRP3–caspase-1–GSDMD pathway, together with microbiota-modulating approaches, including extracellular vesicles, microbial metabolites, and emerging nanomedicine platforms, has demonstrated encouraging efficacy in preclinical models. Collectively, these findings identify the microbiota–inflammasome–pyroptosis axis as a central mechanism linking microbial dysbiosis, immune dysregulation, and epithelial barrier dysfunction in chronic intestinal diseases ( Pérez-Rodríguez and Mercanoglu Taban, 2019 ).

In summary, pyroptosis serves as a critical nexus in chronic intestinal diseases by mediating inflammatory cell death that disrupts epithelial barriers and modulates immune responses. Its regulation is intricately linked with gut microbiota dynamics, creating a complex network that influences disease pathogenesis and therapeutic outcomes. Advances in understanding pyroptosis mechanisms and their interactions with the microbiome have paved the way for novel therapeutic interventions, including small molecule inhibitors, biologics, natural products, stem cell-derived exosomes, and microbiota-targeted therapies. Future research focusing on the precise modulation of pyroptosis and microbiota balance holds promise for improving treatment efficacy and patient quality of life in chronic intestinal disorders ( Figure 3 ).

Pathological involvement of pyroptosis across inflammatory, metabolic, and autoimmune disorders. Aberrant activation of inflammasomes and GSDM-mediated pyroptosis contributes to endothelial dysfunction, tissue injury, and chronic inflammation in diseases such as atherosclerosis, diabetic nephropathy, IBD, and autoimmune conditions.

Research progress on treatment strategies related to thermal death

Current therapeutic strategies targeting pyroptosis across different diseases are systematically summarized in Table 2 , emphasizing both their translational potential and inherent limitations.

Small molecule inhibitors and activators

The development of small molecule modulators targeting the NLRP3 inflammasome and caspase family members represents a pivotal strategy in regulating pyroptosis, with significant therapeutic implications across diverse diseases, including inflammatory disorders and cancer. Small molecule inhibitors of caspase-1, such as NSC697923, have demonstrated potent suppression of enzymatic activity with an IC50 of 1.737 μM, effectively inhibiting NLRP3 inflammasome activation and downstream pyroptotic events in macrophages stimulated by various danger signals ( Cao et al., 2022 ). Mechanistically, NSC697923 not only impedes caspase-1 enzymatic function but also downregulates NLRP3 expression by suppressing NF-κB signaling and disrupting the interaction between RIP2 and pro-caspase-1, thereby blocking inflammasome priming. This dual action culminates in reduced GSDMD cleavage and pyroptosis, which translates into alleviation of inflammation in vivo , as evidenced in a gouty arthritis model. Similarly, manoalide, a selective small molecule inhibitor of NLRP3, acts downstream of potassium and chloride efflux as well as mitochondrial dysfunction, covalently binding to Lys377 of NLRP3 to block its interaction with NEK7, thereby inhibiting inflammasome assembly and ameliorating autoimmune encephalomyelitis in mice ( Li et al., 2022c ). These findings underscore the therapeutic potential of targeting inflammasome components with small molecules to modulate pyroptosis and inflammatory responses.

In the context of cancer therapy, pyroptosis induction via small molecules has emerged as a promising approach to enhance antitumor immunity. For example, the small molecule stabilizer of the MYC G-quadruplex, D089, induces endoplasmic reticulum stress in multiple myeloma cells, triggering both cellular senescence and pyroptosis through caspase-1 activation, GSDMD cleavage, and inflammasome assembly ( Gaikwad et al., 2020 ). The pyroptotic cell death elicited by D089 is characterized by morphological changes distinct from apoptosis, such as cell swelling and membrane rupture, and is accompanied by the release of pro-inflammatory cytokines and DAMPs, which potentiate immune responses against the tumor. Furthermore, engineered nanoplatforms co-delivering small molecule inhibitors targeting PI3K/mTOR and CDK pathways have been designed to induce GSDME-mediated immunogenic pyroptosis in tumor cells, thereby reprogramming the immunosuppressive TME and enhancing the efficacy of ICB therapies ( Yang Q. et al., 2022 ). These nanomicelles exploit the TME’s high glutathione levels for selective activation and deep tumor penetration, illustrating the sophisticated design of small molecule delivery systems to maximize pyroptosis induction and antitumor immunity.

From a translational perspective, several pyroptosis-related inhibitors have already progressed beyond preclinical evaluation. VX-765, an orally bioavailable caspase-1 inhibitor, has been evaluated in clinical studies for epilepsy and inflammatory disorders, demonstrating favorable tolerability and anti-inflammatory activity. In addition, IL-1β-targeting therapies, such as canakinumab and anakinra, have achieved regulatory approval for inflammatory diseases and indirectly validate the therapeutic value of inflammasome-associated pathways in humans ( Ridker et al., 2017a ). Notably, secondary analyses of the CANTOS trial revealed a reduction in lung cancer incidence and mortality among patients receiving canakinumab, suggesting that modulation of pyroptosis-associated inflammatory signaling may have broader clinical implications beyond inflammatory disorders ( Ridker et al., 2017b ).

Nanomaterial-mediated regulation of pyroptosis

Nanomaterials have emerged as powerful tools in the precise modulation of pyroptosis, offering innovative strategies for disease treatment, particularly in cancer and inflammatory disorders. Their unique physicochemical properties—such as size, shape, surface charge, and chemical composition—enable them to interact specifically with cellular components involved in pyroptosis pathways, thereby allowing targeted and controlled induction or inhibition of this form of programmed cell death ( Yu et al., 2025 ). One of the critical advantages of nanomaterials is their ability to serve as carriers for pyroptosis-regulating molecules, ensuring precise delivery to diseased tissues while minimizing systemic toxicity. For example, calcium-based nanomaterials have been engineered to induce calcium overload in tumor cells, disrupting mitochondrial calcium homeostasis and activating caspase-1-mediated cleavage of GSDMD, which triggers pyroptosis ( Li et al., 2025b ). Such nanomodulators can be coated with targeting ligands like hyaluronic acid to enhance tumor specificity and exploit the acidic TME for controlled drug release, thereby improving therapeutic outcomes.

Moreover, nanomaterials can be designed to generate ROS within tumor cells, a key upstream signal in pyroptosis activation. Vanadium-based biodegradable nanoparticles exemplify this approach by catalyzing reactions that elevate intracellular ROS, activating inflammasomes such as NLRP3, and promoting pyroptotic cell death alongside pyroptosis, thereby amplifying antitumor effects ( Zhang J. et al., 2025 ). Similarly, nanozymes with enzyme-mimicking catalytic activities can modulate ROS levels and inflammasome activation, inducing pyroptosis and other regulated cell death pathways to enhance cancer therapy ( Zhang Y. et al., 2023 ). These multifunctional nanomaterials also facilitate combination therapies, integrating photodynamic, photothermal, and chemodynamic modalities to synergistically induce pyroptosis and potentiate immune responses.

In addition to direct induction, nanomaterials can modulate the TIME by promoting pyroptosis-mediated release of pro-inflammatory cytokines and DAMPs, which stimulate DC maturation and cytotoxic T cell infiltration. This immunogenic cell death enhances antitumor immunity and improves the efficacy of ICB therapies ( Xie et al., 2025 ; Ge et al., 2024 ). For instance, platelet-camouflaged nanovehicles have been developed to deliver pyroptosis-inducing agents specifically to bladder cancer cells, triggering caspase-3/GSDME-dependent pyroptosis and remodeling the immunosuppressive microenvironment ( Tian et al., 2024 ). Likewise, nanospiky copper peroxide nanoparticles regulate lactate metabolism and induce both cuproptosis and pyroptosis, further enhancing antigen presentation and antitumor immune responses ( Liu B. et al., 2025 ).

Despite these promising advances, challenges remain in balancing the beneficial and adverse effects of nanomaterial-induced pyroptosis. Overactivation may lead to excessive inflammation or damage to normal tissues, while inadequate targeting can reduce therapeutic efficacy. Strategies such as surface modifications, controlled activation mechanisms, and the use of mRNA-based nanomedicines are being explored to achieve intelligent and precise pyroptosis modulation tailored to the dynamic disease microenvironment ( Yu et al., 2025 ). Furthermore, nanomaterials facilitate the co-delivery of multiple agents, such as epigenetic modulators and inflammasome activators, to enhance pyroptosis by upregulating GSDM expression and inflammasome activation, thereby overcoming tumor resistance and improving immunotherapy outcomes ( Niu et al., 2022 ).

Nanocarriers provide a highly efficient platform for the targeted delivery of pyroptosis modulators, overcoming limitations of conventional small-molecule drugs such as poor solubility, rapid degradation, and off-target toxicity. Various nanocarriers—including liposomes, polymeric nanoparticles, metal-based nanomaterials, and biomimetic vehicles—have been engineered to transport pyroptosis-inducing agents directly to diseased cells. For example, calcium-based nanoparticles have been synthesized via microemulsion methods to deliver calcium ions that induce caspase-1/GSDMD-mediated pyroptosis in tumor cells, simultaneously enhancing antigen presentation and modulating the immunosuppressive TME ( Li et al., 2026 ). Similarly, nanocarriers loaded with nigericin and decitabine have been developed to upregulate GSDMD expression and activate inflammasomes, effectively inducing pyroptosis and systemic antitumor immunity ( Niu et al., 2022 ).

Recent advances in microfluidic technologies have provided powerful tools for the development and optimization of pyroptosis-targeted therapeutics. Microfluidic platforms enable precise control over nanoparticle synthesis, drug encapsulation, and formulation parameters, resulting in improved reproducibility, particle uniformity, and drug loading efficiency. Furthermore, microfluidic tumor-on-chip and organ-on-chip systems facilitate real-time evaluation of pyroptosis-inducing agents under physiologically relevant conditions, accelerating therapeutic screening and personalized treatment development ( Yang et al., 2026 ). Nanoparticle-mediated delivery of immune checkpoint inhibitors has emerged as a promising strategy to enhance pyroptosis-associated antitumor immunity. Conventional systemic administration of anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies is often limited by poor tumor accumulation and immune-related adverse events ( Ghaneialvar et al., 2025 ). Advanced nanoparticle platforms improve intratumoral delivery, prolong circulation time, and reduce off-target toxicity ( Li F. et al., 2023 ).

Regulation of pyroptosis by stem cell-derived exosomes

MSC-Exos have emerged as potent modulators of pyroptosis, a form of inflammatory programmed cell death, thereby offering promising therapeutic avenues for mitigating tissue damage across various diseases. MSC-Exos exert their anti-pyroptotic effects through multiple signaling pathways and molecular cargos, including miRNAs, circRNAs, and proteins, which collectively regulate the activation of inflammasomes and downstream pyroptotic effectors. For instance, in intervertebral disc degeneration (IVDD), MSC-Exos inhibit NLRP3 inflammasome-mediated pyroptosis in nucleus pulposus cells by delivering miR-410, which directly targets NLRP3 mRNA, thus reducing caspase-1 activation and inflammatory cytokine release ( Zhang et al., 2020 ). Similarly, human umbilical cord MSC-derived exosomes (UMSC-Exo) release circHIPK3, which downregulates miR-421 and upregulates FOXO3a, suppressing NLRP3 inflammasome activation and consequent pyroptosis in ischemic skeletal muscle injury models ( Yan et al., 2020 ). In acute lung injury (ALI, MSC-Exos attenuate alveolar macrophage pyroptosis by delivering miRNAs that target caspase-1 and immunoregulatory proteins, thereby reducing inflammation and improving lung function ( Liu P. et al., 2024 ). Moreover, dental follicle stem cell-derived exosomes (DFSC-Exos) have been shown to inhibit NLRP3-mediated pyroptosis in periodontal ligament cells via miR-140-3p, which modulates the DNMT1/SOCS1/NF-κB axis, ultimately reducing osteoclastogenesis and root resorption ( Li et al., 2025c ). In diabetic wound healing, hair follicle MSC-derived exosomal long non-coding RNA H19 suppresses NLRP3 inflammasome activation, promoting keratinocyte proliferation and migration while inhibiting pyroptosis ( Yang H. et al., 2023 ). Furthermore, embryonic stem cell-derived exosomes (ES-Exos) mitigate doxorubicin-induced muscle toxicity by reducing NLRP3 inflammasome components and shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, thereby attenuating pyroptosis and fibrosis ( Dessouki et al., 2020 ). Collectively, these studies demonstrate that MSC-Exos regulate pyroptosis through diverse molecular mechanisms, including miRNA-mediated suppression of inflammasome components, modulation of signaling pathways such as NF-κB, and alteration of macrophage polarization, leading to reduced inflammatory cell death and enhanced tissue repair.

The clinical translation of exosome-based drug delivery systems holds substantial promise due to their inherent biocompatibility, low immunogenicity, and ability to cross biological barriers. MSC-Exos can be engineered to carry specific therapeutic cargos, such as miRNAs or proteins, targeting pyroptosis-related pathways to enhance efficacy and specificity. For example, exosomes modified to overexpress miR-182-5p or miR-23b-3p have shown enhanced cardioprotective effects by targeting GSDMD and NEK7, respectively, thereby inhibiting pyroptosis in myocardial ischemia/reperfusion injury and experimental autoimmune encephalomyelitis models ( Yue et al., 2022 ; Wang J. et al., 2023 ). Additionally, surface modification strategies, such as PEGylation and aptamer conjugation, have been employed to improve exosome circulation time and target specificity, as demonstrated in β-cell-targeting MSC-Exos that suppress NRF2-mediated pyroptosis to improve β-cell function in diabetes ( Xia et al., 2024 ). Despite these advances, challenges remain in large-scale exosome production, standardized isolation methods, and ensuring consistent cargo loading. Furthermore, the heterogeneity of exosome populations and potential off-target effects necessitate rigorous preclinical and clinical evaluation. Nonetheless, the multifunctionality of MSC-Exos, combined with their capacity for precise modulation of pyroptosis, positions them as a versatile platform for developing novel therapies for inflammatory and degenerative diseases. Ongoing research focusing on optimizing exosome engineering, understanding biodistribution, and elucidating long-term safety profiles will be critical to realizing their full clinical potential.

Gene editing and RNA interference technologies

Gene editing and RNA interference (RNAi) technologies have emerged as powerful tools to modulate pyroptosis-related gene expression, offering promising therapeutic strategies for various diseases characterized by dysregulated pyroptosis. Among these, CRISPR-Cas9 technology stands out as a precise and efficient method for targeted gene modification, enabling the knockout or activation of pyroptosis-associated genes to regulate inflammatory cell death pathways. For instance, in psoriasis, CRISPR-Cas9-mediated knockout of CASP1 and CASP5 in keratinocytes delivered via lipid nanoparticles effectively alleviated skin inflammation by suppressing pyroptosis, highlighting the therapeutic potential of gene editing in inflammatory skin disorders ( Xu G. et al., 2025 ). Similarly, in cancer cells, CRISPR-Cas9 gene editing of caspase-8 demonstrated that caspase-8 accumulation and activation are critical for enhancing apoptosis and pyroptosis during combined hyperthermia and cisplatin therapy, suggesting that modulation of caspase-8 expression via gene editing can sensitize tumor cells to cell death ( Zi et al., 2024 ). Moreover, CRISPR-Cas9 gene-edited macrophages lacking caspase-4 or caspase-1 revealed distinct roles in GSDMD cleavage and IL-1β secretion, underscoring the utility of gene editing to dissect pyroptosis mechanisms and identify therapeutic targets ( Wang S. et al., 2022 ). Advancements in base editing technologies, such as bioorthogonally activatable cytosine base editors, enable on-demand and cell-type-specific activation of pyroptosis by inducing truncated GSDME expression, providing a novel approach for precise control of pyroptotic cell death ( Ngai et al., 2022 ).

In addition to gene editing, RNAi and ncRNA-based therapies have been extensively explored to target pyroptosis-related pathways. RNA-binding proteins (RBPs) associated with pyroptosis have been implicated in acute myeloid leukemia prognosis, where risk models based on pyroptosis-related RBPs inform therapeutic strategies ( Bin et al., 2022 ). lncRNAs and miRNAs modulate pyroptosis by regulating key inflammasome components and GSDM proteins. For example, in DN, silencing of lncRNA KCNQ1OT1 reduced oxidative stress and pyroptosis in renal tubular epithelial cells by upregulating miR-506-3p, illustrating the therapeutic potential of targeting ncRNA networks ( Zhu et al., 2020 ). In UC, pericentriolar material 1 (PCM1) was found to promote NLRP3 inflammasome activation and GSDMD-mediated macrophage pyroptosis, implicating RNAi strategies to modulate PCM1 expression as a novel intervention ( Niu et al., 2024 ). Furthermore, lncMCL1 was identified as a critical regulator of neural pyroptosis in epilepsy by stabilizing DDX3X protein through enhanced ubiquitination, suggesting that RNA-based modulation of lncRNAs can attenuate neuroinflammation ( Wang H. et al., 2026 ).

The integration of CRISPR-Cas9 gene editing with RNAi approaches has also been applied in cancer immunotherapy. A nano-CRISPR scaffold delivering sgRNA to activate endogenous GSDME expression, combined with cisplatin release, induced pyroptosis and enhanced antitumor immunity, demonstrating a synergistic strategy leveraging gene editing and chemotherapy ( Wang N. et al., 2023 ). Additionally, CRISPR-Cas9-mediated knockout of GSDME or caspase-3 in cancer cells modulated pyroptosis and apoptosis balance, influencing therapeutic outcomes ( Xian et al., 2024 ; Tan et al., 2022 ). These studies underscore the versatility of gene editing and RNAi technologies in fine-tuning pyroptosis pathways for disease treatment.

Moreover, delivery systems facilitating gene editing and RNAi are critical for clinical translation. For example, albumin-based nanoparticles have been engineered to protect and deliver CRISPR-Cas9 components targeting PAR2, effectively mitigating cytokine storm by attenuating TLR4/NF-κB signaling and pyroptosis ( Li J. et al., 2025 ). Similarly, α-synuclein-gold nanoparticle conjugates enable rapid and nondisruptive DNA transfection, offering a platform for delivering genes such as granzyme A to induce pyroptosis ( Park et al., 2025 ). These innovative delivery modalities enhance the specificity and efficiency of gene editing and RNAi therapies targeting pyroptosis.

In addition to gene-editing and RNA-based approaches, enhancer elements have recently gained attention as important regulators of therapeutic gene expression. Natural tissue-specific enhancers and engineered synthetic enhancers have been incorporated into gene delivery constructs to achieve selective expression in particular cell types while minimizing off-target effects. Such strategies are particularly attractive for pyroptosis-related interventions, where excessive or systemic activation of inflammasome signaling may result in undesirable inflammatory toxicity ( Najafi et al., 2024 ).

Combined immunotherapy and pyroptosis induction

The integration of pyroptosis induction with ICB therapy represents a promising frontier in cancer treatment, aiming to overcome the limitations of current immunotherapies. Pyroptosis, a highly inflammatory form of programmed cell death mediated by GSDM proteins, enhances tumor immunogenicity by releasing TAAs, DAMPs, and proinflammatory cytokines such as IL-1β and IL-18. These factors collectively remodel the TME from an immunosuppressive “cold” state to an immunoreactive “hot” state, thereby potentiating the efficacy of ICIs like anti-PD-1/PD-L1 and CTLA-4 antibodies. Multiple studies have demonstrated that pyroptosis activation in tumor cells promotes DC maturation, increases infiltration of cytotoxic CD8 + T cells and NK cells, and reduces immunosuppressive cell populations within tumors, which synergistically enhance antitumor immunity and improve clinical outcomes ( Wang W. et al., 2022 ; Bourne and Taabazuing, 2024 ; Zhang et al., 2024 ).

Recent advances in nanotechnology have enabled precise and controlled induction of pyroptosis within tumors, minimizing off-target effects and enhancing immunotherapeutic synergy. Nanomaterial-based delivery systems can co-deliver pyroptosis inducers and ICIs, or be engineered to respond to tumor-specific stimuli such as ROS or acidic pH, thereby achieving spatiotemporal control over pyroptosis activation. For instance, ROS/GSH dual-responsive nano-prodrugs combining chemotherapeutic agents and photosensitizers have been shown to induce GSDME-mediated pyroptosis upon photodynamic therapy, leading to enhanced DC maturation, increased cytotoxic T cell infiltration, and improved efficacy of ICB therapy ( Xie et al., 2025 ; Ji et al., 2024 ; Xiao et al., 2021 ). Similarly, calcium ion nanomodulators and biodegradable upconversion nanoparticles have been developed to trigger mitochondrial calcium overload or ionic imbalances that activate pyroptosis and subsequent antitumor immune responses ( Qi et al., 2025 ; Ding et al., 2021 ).

Clinical and preclinical data further support the prognostic and predictive value of pyroptosis-related signatures in various cancers, including glioma, bladder cancer, breast cancer, and lung squamous cell carcinoma. High pyroptosis scores correlate with increased infiltration of CD8 + T cells, elevated expression of immune checkpoints, and better responses to immunotherapy, suggesting that pyroptosis status can guide patient stratification and therapeutic decisions ( Zeng et al., 2022 ; Wu et al., 2021b ; Deng et al., 2022 ; Zhang Q. et al., 2022 ). Moreover, combinatory strategies that induce pyroptosis alongside ICB have demonstrated synergistic effects, converting immunologically “cold” tumors into “hot” ones and overcoming resistance to checkpoint blockade ( Gao et al., 2022 ; Duan et al., 2025 ).

However, challenges remain in balancing the extent of pyroptosis induction to maximize antitumor immunity while minimizing systemic inflammation and tissue damage. Innovative approaches such as enzymatically switchable pyroptosis-inducing polymer conjugates and tunable nanomodulators offer precise control over pyroptosis levels, enhancing safety and therapeutic index ( Chen et al., 2025 ; Ghosh et al., 2026 ). Additionally, understanding the interplay between pyroptosis and other forms of regulated cell death, as well as the epigenetic regulation of pyroptosis-related genes, may provide novel targets to further enhance immunotherapy outcomes ( Zhang R. N. et al., 2023 ; Gao et al., 2022 ).

In conclusion, the mechanistic crosstalk between pyroptosis and immune cells orchestrates a potent antitumor immune response. By promoting antigen release, inflammatory cytokine secretion, and immune cell activation, pyroptosis synergizes with immunotherapies to overcome tumor immune evasion ( Figure 4 ). However, current pyroptosis-targeted therapeutic strategies differ substantially in their translational maturity. Small-molecule inhibitors of inflammasome- or cytokine-related pathways have the clearest clinical relevance, particularly because IL-1-targeted therapies and caspase-1 inhibitors provide human evidence that inflammasome-associated inflammation can be pharmacologically modulated. In contrast, nanomaterials, extracellular vesicles, and gene-regulation platforms offer greater tissue specificity and mechanistic flexibility but remain largely preclinical. Their clinical translation is still limited by delivery efficiency, biodistribution, manufacturing reproducibility, long-term safety, and the risk of excessive or off-target inflammatory activation.

Regulatory network controlling pyroptosis activation and execution. Pyroptosis is fine-tuned by upstream danger signals, intracellular signaling pathways, post-translational modifications, and epigenetic mechanisms, including ncRNAs. These regulatory layers determine the intensity, duration, and biological outcome of pyroptotic responses.

Application of pyroptosis in disease diagnosis and prognosis

Screening and validation of pyroptosis-related biomarkers

Elevated expression levels of these GSDMs and cytokines have been clinically correlated with disease activity and prognosis. For instance, in Sjögren’s Syndrome, increased expression of GSDMD, along with pyroptosis-associated genes GZMA and GBP1, was observed in salivary gland tissues, and their combined diagnostic value was high (AUC = 0.8858), indicating their potential as biomarkers for inflammation-related pyroptosis ( Zhang K. et al., 2023 ). Similarly, in bladder cancer, key pyroptosis-related genes including CASP8, NLRP3, and IL18 were found to be differentially expressed, and immune infiltration analysis revealed significant involvement of immune cells such as CD8 + T cells and macrophages, underscoring the clinical relevance of these biomarkers in tumor immunity and progression ( Li P. et al., 2025 ). In RA, CASP8 emerged as a common biomarker linking ferroptosis and pyroptosis, with its expression validated in FLSs; furthermore, quercetin was identified as a potential therapeutic agent targeting CASP8, highlighting the translational potential of pyroptosis biomarkers ( Zheng et al., 2023 ).

The integration of pyroptosis-related gene expression into scoring systems has enhanced prognostic assessments in oncology. In CRC, a pyroptosis-related gene signature including RSAD2 was developed, which independently predicted patient prognosis and correlated with TIME status, thereby offering a valuable prognostic biomarker and immunotherapy response indicator ( Li Y. et al., 2024 ). Similarly, in gastric cancer, a pyroptosis risk score (PRS) constructed from four pyroptosis-related genes (BATF2, PTPRJ, RGS1, VCAN) demonstrated robust prognostic performance and was associated with immune cell infiltration patterns that predicted neoadjuvant immunotherapy efficacy ( Wang J. B. et al., 2024 ). In TNBC, a pyroptosis scoring system (Ps-score) stratified patients into subtypes with distinct immunological features and therapeutic responses, validated by both bulk and single-cell RNA sequencing (scRNA-seq) data, emphasizing the clinical utility of pyroptosis-based prognostic models ( Li et al., 2022d ).

Moreover, in melanoma, a pyroptosis-based model constructed through LASSO regression effectively predicted clinical benefit from immunotherapy, with high pyroptosis scores correlating with an immune-inflamed TME and improved survival outcomes, thus serving as a reliable biomarker for treatment stratification ( Wu G. et al., 2023 ). In lung adenocarcinoma, pyroptosis-related lncRNA signatures were also identified as prognostic biomarkers, further demonstrating the expanding scope of pyroptosis markers beyond protein-coding genes ( Wang P. et al., 2024 ).

Emerging evidence suggests that pyroptosis-associated molecules may serve as valuable liquid biopsy biomarkers. Circulating gasdermin family proteins, inflammasome components, and inflammatory cytokines such as IL-1β and IL-18 reflect ongoing pyroptotic activity and have been associated with tumor progression, immune status, and therapeutic response. Elevated levels of these molecules have been reported in multiple malignancies and may provide complementary diagnostic information beyond conventional biomarkers ( Salehnia et al., 2026 ).

Development of pyroptosis activity detection techniques

The advancement of pyroptosis activity detection techniques has been pivotal in elucidating the molecular mechanisms and pathological roles of pyroptosis in various diseases, especially cancer and inflammatory disorders. Single-cell sequencing and multi-omics analysis technologies have emerged as powerful tools to dissect pyroptosis at cellular resolution and to integrate diverse molecular layers, providing comprehensive insights into pyroptosis regulation and its heterogeneity across cell types. For instance, scRNA-seq has been employed to identify pyroptosis-related gene expression signatures in specific immune cell populations within disease microenvironments. In necrotizing enterocolitis (NEC), scRNA-seq revealed increased macrophage abundance with a distinct cluster exhibiting elevated pyroptosis scores, highlighting the role of pyroptosis in disease progression and identifying TREM1 as a potential therapeutic target ( Zhang P. et al., 2025 ). Similarly, in ischemic stroke, bioinformatics analysis combined with in vivo and in vitro experiments identified Annexin A3 (ANXA3) as a pyroptosis-related biomarker, with silencing of ANXA3 alleviating pyroptosis and microglial activation ( Liu L. et al., 2023 ). These studies illustrate how single-cell transcriptomics, coupled with protein-level validation, can pinpoint cell-type-specific pyroptosis pathways and candidate regulators.

Multi-omics approaches, integrating transcriptomics, proteomics, epigenomics, and metabolomics, further enhance the understanding of pyroptosis mechanisms. These integrative analyses enable the identification of key genes like NLRP3, caspase-1, and GSDMs, and their regulatory networks, including ncRNAs, and epigenetic modifications, which govern pyroptotic responses. Moreover, molecular docking and dynamics simulations have been applied to predict and validate interactions between small molecules and pyroptosis-related proteins, facilitating drug discovery efforts ( Lestari et al., 2025 ).

In the context of body fluid detection, several methods have been developed to monitor pyroptosis-related molecules non-invasively, which is crucial for clinical diagnosis and therapeutic monitoring. Enzyme-linked immunosorbent assays (ELISA) and Western blotting are routinely used to measure levels of pyroptosis-associated cytokines such as IL-1β and IL-18, as well as cleaved GSDM fragments in serum or plasma samples. For example, elevated serum IL-1β and IL-18 levels have been correlated with pyroptosis activation in sepsis, DN, and myocardial injury ( Ye et al., 2025 ; Wang S. et al., 2024 ; Yao et al., 2025 ). Lactate dehydrogenase (LDH) release assays serve as indicators of cell membrane rupture during pyroptosis and have been used in both in vitro and in vivo studies to assess pyroptotic cell death ( Duan et al., 2024 ; Huang et al., 2024 ). In addition, novel molecular probes and fluorescent reporters have been developed for live-cell imaging of pyroptosis, enabling real-time monitoring of caspase activation and GSDM pore formation ( Ali and Wang, 2024 ; Wang X. et al., 2023 ). These probes, combined with near-infrared fluorescence imaging, have been successfully applied in cancer chemo-immunotherapy models to predict therapeutic efficacy by visualizing intratumoral pyroptosis ( Wang X. et al., 2023 ).

Furthermore, bioinformatics analyses of circul ating extracellular vesicles and exosomes have identified pyroptosis-related miRNAs and lncRNAs as potential biomarkers detectable in body fluids, offering minimally invasive diagnostic options. For instance, exosomal miR-25-3p derived from platelet-rich plasma has been shown to alleviate chondrocyte pyroptosis in osteoarthritis, suggesting its potential as a therapeutic biomarker ( Wang J. et al., 2025 ). Similarly, circulating histone levels correlated with endothelial pyroptosis and septic shock severity, providing a link between pyroptosis markers in blood and disease prognosis ( Beltrán-García et al., 2022 ).

Value of pyroptosis markers in monitoring therapeutic response

The quantification and dynamic monitoring of pyroptosis markers have emerged as promising tools for predicting and evaluating therapeutic responses in various diseases, particularly cancer and inflammatory conditions. Pyroptosis, an inflammatory form of programmed cell death mediated by gsdms and inflammasomes, plays a dual role in modulating treatment efficacy by directly inducing tumor cell death and shaping the immune microenvironment. Several studies highlight the predictive value of pyroptosis levels in assessing chemotherapy and immunotherapy outcomes. For instance, in cancer therapy, the expression of GSDM family members, especially GSDME and GSDMD, correlates with enhanced sensitivity to chemotherapeutic agents and ICIs. The deubiquitinating enzyme USP48 stabilizes GSDME, promoting pyroptosis and augmenting the efficacy of PD-1 blockade in tumor models, indicating that higher pyroptosis activity predicts better immunotherapeutic response ( Ren Y. et al., 2023 ). Similarly, in head and neck squamous cell carcinoma, tumor-intrinsic SIRPA expression suppresses GSDME-mediated pyroptosis, reducing chemotherapy and immunotherapy effectiveness; thus, pyroptosis markers can stratify patients likely to benefit from these treatments ( Song A. et al., 2025 ). Furthermore, pyroptosis-related gene signatures have been developed to classify patients into subgroups with distinct immune infiltration profiles and therapeutic responses. In glioma, a pyroptosis regulation score (PSscore) correlates with tumor mutational burden, immune cell infiltration, and response to anti-PD-1 therapy, underscoring its prognostic and predictive utility ( Fan et al., 2022 ). In metastatic melanoma, pyroptosis-related gene scores associate with immune-enriched TMEs and improved immunotherapy outcomes ( Chen et al., 2024b ). These findings suggest that baseline pyroptosis levels can predict treatment efficacy, while longitudinal monitoring of pyroptosis dynamics can guide personalized therapy adjustments. For example, fluorescence probes detecting mitochondrial oxidative stress and pyroptosis activation provide real-time feedback on chemotherapy-induced tumor cell death, enabling precise therapeutic monitoring ( Deng et al., 2025 ). In autoimmune and inflammatory diseases, urinary biomarkers linked to pyroptosis, such as vitronectin in juvenile SLE, offer non-invasive means to monitor disease activity and treatment response ( Zhang et al., 2022c ). Moreover, in sepsis and acute organ injuries, circulating pyroptosis markers like GSDMD and inflammasome components reflect disease progression and therapeutic efficacy, facilitating early intervention and prognosis assessment ( Li et al., 2025e ; Guo et al., 2026 ). Collectively, these studies demonstrate that pyroptosis markers serve as valuable indicators for predicting chemotherapy and immunotherapy outcomes and for dynamic monitoring to optimize individualized treatment strategies. Integration of pyroptosis biomarker profiling into clinical practice holds promise for enhancing precision medicine across oncology and inflammatory disorders ( Figure 5 ).

Current and emerging therapeutic approaches targeting pyroptosis pathways. Strategies include inhibition of inflammasomes and GSDMs to suppress excessive inflammation, as well as deliberate induction of pyroptosis to enhance antitumor immunity. Nanomedicine, RNA-based therapies, and combination strategies further expand the therapeutic landscape.

Challenges and future prospects in pyrolysis research

Safety and specificity issues in clinical translation

In cancer therapy, pyroptosis inducers like acevaltrate have demonstrated efficacy in overcoming drug resistance by promoting caspase-3/GSDME-dependent pyroptosis in myeloma cells, yet their pro-inflammatory nature raises concerns about systemic toxicity and cytokine release syndrome ( Wang Y. et al., 2025 ). The risk of uncontrolled inflammation is also evident in sepsis, where pyroptosis contributes to multi-organ injury through excessive cytokine storm and tissue damage; thus, therapeutic modulation requires a delicate balance to avoid exacerbating systemic toxicity ( Liu and Liang, 2025 ). Moreover, nanomaterials such as nanodiamonds have been reported to induce platelet pyroptosis and thrombocytopenia via NLRP3 inflammasome activation, highlighting the potential hematological side effects of pyroptosis-inducing agents ( Hung et al., 2022 ). Natural compounds like luteolin and metformin have shown favorable safety profiles in modulating pyroptosis-related pathways, suggesting that careful selection and dosing of pyroptosis modulators can mitigate adverse effects ( Sun et al., 2025 ; Zhang et al., 2021b ). Nonetheless, the inflammatory amplification inherent to pyroptosis necessitates rigorous preclinical and clinical evaluation to minimize risks of excessive immune activation and off-target toxicity in patients. Achieving precise and stable delivery of pyroptosis modulators is paramount to enhancing therapeutic efficacy while minimizing systemic side effects. Conventional systemic administration often results in suboptimal drug concentrations at target tissues and off-target activation of pyroptosis, leading to safety concerns. To address this, advanced delivery platforms such as nanoparticles, liposomes, and engineered viral vectors have been developed to improve targeting specificity and pharmacokinetic stability. For instance, recombinant human heavy chain ferritin (HFn) nanocages loaded with 5-fluorouracil (5-FU@HFn) demonstrated selective uptake by chronic myeloid leukemia cells via CD71-mediated endocytosis, enhancing pyroptosis induction and reducing off-target toxicity ( Yuan et al., 2025 ). Similarly, nanoliposomes responsive to pyroptotic cell signals have been engineered to release anti-pyroptotic drugs on-demand within inflamed tissues, exploiting GSDME interactions to achieve self-adaptive drug release and improved therapeutic outcomes in autoimmune inflammatory diseases ( Xu et al., 2024 ). In cancer therapy, bioorthogonal pyroptosis nanoregulators facilitate in situ photosensitizer synthesis and autophagy inhibition specifically in tumor mitochondria, thereby enhancing pyroptosis efficacy while sparing normal tissues ( Zhang W. et al., 2023 ). Moreover, erythrocyte membrane-camouflaged Pt (II) layered double hydroxide nanocages (RmPLH) prolong systemic circulation, evade immune clearance, and enable tumor-targeted sonodynamic therapy that synergizes with ICIs ( Wu Y. et al., 2025 ). Viral delivery systems have also been optimized to induce pyroptosis selectively in tumor cells; for example, oncolytic adenoviruses armed with neutrophil elastase or PPE proteins promote macrophage polarization and effector T cell infiltration, enhancing antitumor immunity with controlled activation ( Wang S. et al., 2025 ). Despite these advances, challenges remain in ensuring the stability of delivery vehicles under physiological conditions, avoiding premature drug release, and achieving precise spatiotemporal control over pyroptosis induction. Stability issues can lead to rapid drug degradation or unintended activation, compromising safety and efficacy. Therefore, ongoing research focuses on refining targeting ligands, stimuli-responsive materials, and combination strategies to enhance delivery precision and maintain therapeutic stability in clinical settings.

Development and optimization of novel therapeutic strategies

Given pyroptosis’s complex involvement in tumor progression and immune modulation, combination therapies are designed to simultaneously target multiple nodes within the pyroptotic and associated signaling pathways to synergistically enhance antitumor immunity and overcome tumor resistance.

For instance, the integration of pyroptosis inducers with ICIs has shown promise in transforming immunologically “cold” tumors into “hot” ones by enhancing CD8 + T cell infiltration and activity ( Ren Y. et al., 2023 ; Zhang Q. et al., 2022 ). Moreover, combinatorial regimens involving canonical pyroptosis activation (via caspase-1/GSDMD) alongside modulation of apoptosis or autophagy checkpoints have been proposed to circumvent tumor cell survival mechanisms that dampen pyroptotic efficacy ( Zhang W. et al., 2023 ; Hu et al., 2023 ). The use of small-molecule inhibitors or activators targeting inflammasomes (e.g., NLRP3), caspases, and GSDM family members enables fine-tuning of pyroptotic responses, balancing proinflammatory effects to avoid excessive tissue damage while maximizing tumor cell death ( Liu Q. et al., 2026 ; Shang et al., 2025 ).

Additionally, repurposing existing drugs with known pyroptosis-modulating properties, such as metformin, simvastatin, and curcumin, in combination with conventional chemotherapeutics, has been explored to potentiate pyroptosis-mediated tumor suppression while reducing systemic toxicity ( Wu H. et al., 2022 ; Eldken et al., 2025 ). The identification of molecular regulators like USP48, which stabilizes GSDME to promote pyroptosis and enhance immunotherapy efficacy, further supports the rationale for multi-target combination approaches ( Ren Y. et al., 2023 ). These strategies are underpinned by comprehensive molecular profiling and bioinformatics analyses to tailor therapies based on tumor-specific pyroptosis signatures and immune microenvironment characteristics, thereby advancing precision medicine paradigms ( Ouyang et al., 2024 ; Liang et al., 2021 ).

Despite promising preclinical data, challenges remain in optimizing dosing regimens, minimizing off-target inflammation, and managing the dualistic nature of pyroptosis in cancer and inflammatory diseases. Future directions emphasize the integration of pyroptosis-targeting agents with immunomodulatory drugs, epigenetic modulators, and metabolic regulators to achieve sustained therapeutic responses with manageable safety profiles ( Tuncer and Alcan, 2023 ; Hou et al., 2025 ). Overall, multi-target combination therapies hold significant potential to harness the full therapeutic benefit of pyroptosis modulation across diverse pathological contexts.

Future research directions and technological innovations

The rapid expansion of pyroptosis research has revealed its pivotal role in diverse diseases, especially cancer and inflammatory disorders, positioning it as a promising therapeutic target. However, the complexity of pyroptosis pathways and the multifaceted roles of GSDM proteins necessitate advanced strategies to identify effective modulators. High-throughput screening (HTS) technologies offer powerful platforms to systematically evaluate large compound libraries for pyroptosis modulators, enabling the discovery of novel small molecules or biologics that can specifically induce or inhibit pyroptosis. Coupling HTS with artificial intelligence (AI) and machine learning algorithms further enhances drug discovery by enabling predictive modeling of compound-target interactions, optimizing lead compound selection, and accelerating the identification of candidates with favorable pharmacokinetic and safety profiles. Additionally, in silico methods integrating databases of pyroptosis-related genes, proteins, and pathways facilitate the identification of druggable targets and the rational design of inhibitors or activators ( Zhang L. et al., 2025 ; Zhu et al., 2025 ). The integration of HTS and AI-assisted drug design holds great potential to overcome current challenges in pyroptosis-targeted therapy development, such as specificity, efficacy, and toxicity, ultimately accelerating the translation of pyroptosis modulators into clinical applications.

Emerging evidence highlights the intricate crosstalk between pyroptosis and immunometabolic pathways within the TME, which critically influences tumor progression, immune evasion, and therapeutic responses. Pyroptosis can modulate the release of proinflammatory cytokines and danger signals, reshaping the TME by affecting immune cell infiltration, angiogenesis, and stromal interactions ( Wang H. et al., 2024 ; Liu W. et al., 2023 ). Immunometabolism, encompassing metabolic reprogramming of immune and tumor cells, governs the functional state of immune effectors and the inflammatory milieu. Studies suggest that metabolic intermediates and oxidative stress regulate pyroptosis activation, while pyroptosis in turn influences metabolic pathways, creating feedback loops that impact tumor immunity and inflammation ( Wang J. et al., 2024 ; Cao et al., 2023 ). Comprehensive mechanistic investigations are needed to elucidate how pyroptosis intersects with immunometabolic networks and TME components, including cancer-associated fibroblasts, MDSCs, and Tregs.

Translating pyroptosis research into clinical practice requires well-designed clinical trials that account for the heterogeneity of diseases and patient-specific factors. Given the dual roles of pyroptosis in disease pathogenesis—both protective and detrimental depending on context—precision medicine approaches are essential. Biomarker-driven stratification based on pyroptosis-related gene expression profiles, inflammasome activity, and GSDM expression can identify patient subgroups likely to benefit from pyroptosis-targeted therapies ( Zhou et al., 2021 ; Chen et al., 2023 ). Incorporation of pyroptosis scoring systems and molecular signatures into trial design can optimize inclusion criteria and therapeutic monitoring. Moreover, integrating multi-omics data and AI-driven predictive models can guide individualized treatment regimens that combine pyroptosis modulators with immunotherapies, chemotherapy, or targeted agents. The development of novel delivery systems, such as nanomedicine platforms and MSC-Exos, offers opportunities for targeted and controlled modulation of pyroptosis in specific tissues, enhancing efficacy and minimizing systemic toxicity ( Yu et al., 2025 ; Yang et al., 2025 ). Future clinical trials should also consider the timing and dosing of pyroptosis-inducing agents to balance antitumor immunity and inflammation-related adverse effects. Collectively, these strategies will facilitate the construction of personalized therapeutic regimens, maximizing clinical benefits while mitigating risks associated with pyroptosis modulation ( Figure 6 ).

Challenges and future directions for pyroptosis-based therapies. Key considerations include disease-specific heterogeneity, safety concerns related to excessive inflammation, precision targeting, and patient stratification. Addressing these challenges is essential for translating pyroptosis modulation into clinical practice.

Conclusion

Pyroptosis has emerged as a pivotal form of inflammatory programmed cell death that influences a broad spectrum of diseases, including cancer, cardiovascular disorders, metabolic diseases, and autoimmune conditions. Growing evidence indicates that pyroptosis functions as a double-edged sword: while controlled activation can promote host defense, tissue repair, and antitumor immunity, excessive or chronic pyroptosis may drive pathological inflammation and disease progression. The ultimate biological outcome is highly context dependent and influenced by factors such as disease type, disease stage, genetic background, and immune microenvironment composition.

Recent advances in pyroptosis research have identified numerous therapeutic opportunities, including small-molecule inhibitors, extracellular vesicle-based therapies, nanomedicine platforms, gene regulation technologies, and emerging precision drug-delivery systems. In parallel, pyroptosis-related biomarkers, scoring systems, and liquid biopsy approaches are showing increasing promise for disease diagnosis, prognostic stratification, treatment monitoring, and prediction of therapeutic responses.

Despite these advances, several challenges remain. Most current evidence is derived from preclinical studies, while prospective clinical validation remains limited. In addition, substantial heterogeneity exists in pyroptosis biomarkers and assessment methods, and the complex crosstalk between pyroptosis and other cell death pathways continues to complicate mechanistic interpretation and therapeutic targeting.

Future studies should focus on defining the context-specific determinants of pyroptosis, establishing standardized biomarkers, and translating emerging therapeutic strategies into clinically validated interventions. Such efforts will be essential for harnessing the full potential of pyroptosis in precision medicine and next-generation therapeutic development.

Edited by: Jiri Novotny , Charles University, Czechia

Reviewed by: Christopher Montemagno , Centre Scientifique de Monaco, Monaco

Mohammad Amin Khalilzad , National Institute for Genetic Engineering and Biotechnology, Iran

Author contributions

YS: Visualization, Conceptualization, Writing – original draft. QZ: Writing – original draft, Conceptualization, Visualization. YY: Writing – review and editing, Data curation. WC: Data curation, Writing – review and editing. MiL: Writing – review and editing, Data curation. FJ: Writing – review and editing, Data curation. MaL: Writing – review and editing, Data curation. YZ: Writing – review and editing, Conceptualization, Supervision.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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