Emerging role of PANoptosis in pathogen infection and systemic diseases.

Introduction
Programmed cell death (PCD) is a crucial mechanism that preserves cellular as well as tissue homeostasis by eliminating superfluous or damaged cells. Apoptosis, pyroptosis, and necroptosis have traditionally been regarded as independent death pathways, each playing unique roles in development, immunity, and tissue balance (Karki et al. 2021a; Oh et al. 2023). Mounting evidence indicates significant molecular intersections and synergistic regulatory interactions among these cell death types during pathogen infection, inflammation, tumor progression, and other complex pathological conditions, suggesting the existence of a more integrated cell death regulatory network (Malireddi et al. 2020a). The characteristics of these distinct cell death types are summarized in Table 1.

In 2019, the Kanneganti team introduced the concept of "PANoptosis," which is regulated by multi-protein complexes termed PANoptosome. PANoptosis simultaneously exhibits features of pyroptosis, apoptosis, and necroptosis (Malireddi et al. 2019). The execution of PANoptosis is mediated by specific PANoptosome complexes, including Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which detect danger signals, such as Z-type nucleic acids via the Zα domain, and subsequently activate downstream effectors, including Caspase-1/3/8 and phosphorylated mixed lineage kinase domain-like protein (MLKL), forming a robust and complex immune response network (Karki et al. 2022; Sharma et al. 2023).
PANoptosis plays a pivotal role in antiviral, antifungal, and antibacterial immune responses and contributes to the progression of systemic diseases, including acute kidney injury (AKI), myocardial injury, neurodegenerative disorders, ocular diseases, and various malignant tumors (Karki et al. 2021a, 2022; Kesavardhana et al. 2020). Its multiple functions enable elimination of infectious sources while potentially triggering excessive inflammation, making PANoptosis a potential target for therapeutic intervention. This review aimed to systematically summarize the molecular mechanism, pathophysiological roles, and therapeutic significance of PANoptosis, providing a foundation for future translational and clinical applications.

Mechanism of PANoptosis
PANoptosis ('P' for pyroptosis, 'A' for apoptosis, and 'N' for necroptosis) represents the integrated regulation of these three fundamental PCD pathways (Tweedell et al. 2024; Christgen et al. 2020). Specifically, PANoptosis is mediated by PANoptosomes, a multi-protein complex that incorporates components from pyroptosis, apoptosis, and necroptosis to form an intricate molecular platform orchestrating cell death.
Apoptosis, the most extensively studied form of PCD, was first described in 1972. It is genetically regulated and minimizes damage to surrounding tissues. Apoptosis primarily relies on two core mechanisms: extrinsic signaling via death receptors and intrinsic signaling originating from mitochondria. The extrinsic pathway is initiated by ligand binding to cell-surface death receptors, such as Fas and tumor necrosis factor receptor 1, which activate the Caspase cascade. The intrinsic pathway is triggered by intracellular stress signals, leading to increased mitochondrial membrane permeability, release of pro-apoptotic factors, and subsequent Caspase activation. Both pathways rely on Caspase activation but engage different downstream Caspases. Although apoptosis was originally considered non-inflammatory, it can induce inflammatory responses in certain cell types (Elmore 2007).
When Caspase activation is inhibited by viral infection or chemical treatment, necroptosis can be activated as an alternative cell death pathway. Unlike apoptosis, necroptosis leads to rupture of the plasma membrane and the leakage of intracellular content, resulting in inflammation. In particular, inhibition of Caspase-8, a key apoptotic initiator, triggers necroptosis via the receptor-interacting serine/threonine-protein kinase 3 (RIPK3)–MLKL complex. This regulatory interplay maintains a balance among PCD pathways, providing a substitute cell death mechanism when apoptosis is blocked. Recent studies indicate that RIPK3 activation not only phosphorylates MLKL but also simultaneously activates the nucleotide-binding and the leucine-rich repeat and pyrimidine domain-containing protein 3 (NLRP3) inflammasome and Caspase-1, underscoring the complex interplay among these molecular players (Zhu et al. 2021). Furthermore, MLKL activation promotes NLRP3 inflammasome formation, linking necroptosis to the pyroptosis pathway (Zhu et al. 2021).
Pyroptosis is initiated by Caspase-1 and mediated by GSDMD. In the absence of GSDMD, Caspase-1 induces apoptosis via the Bid-Caspase-9-Caspase-3 signaling pathway (Zuo et al. 2020). These evolving and interconnected cell death mechanisms ensure that the body can respond effectively to pathogens and other cellular threats by utilizing alternative PCD pathways when specific proteins are compromised or suppressed.
The PANoptosome is a multi-protein complex comprising three functional modules: sensor proteins (e.g., ZBP1 and NLRP3), adapter proteins (e.g., apoptosis-associated speck-like protein containing a CARD [ASC] and Fas-associated death domain protein [FADD]), and effector proteins (e.g., RIPK1, RIPK3, Caspase-1/8). Its activation mechanism involves sensor proteins detecting specific pathogenic or danger signals. Adapter proteins then oligomerize to form a molecular bridge, recruiting and linking the sensors to the effector proteins. Ultimately, the effector proteins are activated and function as the executioners of the cell death program, cooperatively initiating downstream death-signaling pathways. However, the mechanisms of certain upstream PANoptotic molecules remain unclear (Wang and Kanneganti 2021). To date, five canonical PANoptosomes components are identified and shown in Fig. 1A. ZBP1, an innate immune receptor, plays a key role in IAV infection by triggering PANoptosomes assembly and initiating PANoptosis. This process activates Caspase-1/3/8 and induces necroptosis with the biomarker of MLKL phosphorylation (Zhu et al. 2024). The interaction between ZBP1 and adenosine deaminase acting on RNA 1 is particularly critical for inhibiting PANoptosis via attenuating the forming of ZBP1–RIPK3 complex. The assembly of PANoptosomes into a molecular platform is a hallmark of PANoptosis, activating molecules involved in pyroptosis, apoptosis, and necroptosis (Zhu et al. 2023; Huang et al. 2025). This intricate network underscores the complexity of cell death regulation in biological systems.
PANoptosis provides a comprehensive perspective on PCD, wherein these processes are integrated and concurrently regulated to maintain cellular homeostasis and defend against diverse threats (Fig. 1B). Although PANoptosis shares some features with other forms of cell death, it cannot be solely defined by pyroptosis, apoptosis, or necroptosis. PANoptosis is typically triggered by pathogenic infections, inflammatory conditions, or cellular stress, with ZBP1 serving as a key regulator. The critical role of PANoptosis in innate immunity has been highlighted by the study of severe acute respiratory syndrome 2 (SARS-CoV-2). ZBP1-mediated inflammatory cell death reduces the effectiveness of interferon (IFN) therapy (Schifanella et al. 2023). Notably, the increase in lethality observed in mice infected with β-coronavirus and treated with IFN-β is inhibited by deletion of ZBP1 or its Zα domain, suggesting that modulation of ZBP1 activity could enhance the effectiveness of IFN therapy (Karki et al. 2022). In addition, PANoptosis contributes to overcoming therapeutic resistance and activating anti-tumor immune responses. PANoptosis is closely associated with tumor microenvironment (TME) where releases intracellular components such as IL-1β and TNF-α during PANoptosis activation, which regulate the antigenicity of cancer cells and the responsiveness of immune cells, thereby exerting a dual role in either promoting or suppressing tumor progression (Gao et al. 2024). Studies have demonstrated that TNF-α and IFN-γ synergistically induce PANoptosis in multiple human cancer cell lines and inhibit tumor growth in vivo. Moreover, PANoptosis indices correlate with the TME, immune cell recruitment dynamics, and immunotherapy, suggesting their potential as biomarkers for predicting immunotherapy efficacy (Zhu et al. 2023).
As a complex inflammatory cell death pathway, PANoptosis plays multifaceted roles in diseases, ranging from cancer to inflammatory disorders. Despite recent advances in elucidating its mechanisms, key questions remain regarding the assembly of the PANoptosome and its context-specific functions. Therefore, ongoing research is focused on clarifying these molecular details to support the translation of PANoptosis-related discoveries into therapeutic strategies.

Pathogen-induced ZBP1-dependent PANoptosis

Virus-induced ZBP1-dependent PANoptosis
ZBP1 recognizes Z-form nucleic acids (such as Z-RNA or Z-DNA) through its N-terminal Zα domain. RIP homotypic interaction motif (RHIM) in ZBP1 C terminal can bind to RIPK1 and RIPK3, thereby triggering downstream necroptotic or inflammatory signaling pathways (Fig. 1A). ZBP1 serves dual functions in antiviral immunity, as it restricts viral replication while also potentially promoting excessive inflammation and tissue damage.
Innate immunity constitutes the first line of defense against viral infections in host cells. Pattern recognition receptors (PRRs) are critical initiators of innate immune responses. These receptors recognize microbial molecular motifs and host-derived alarmins, triggering signaling cascades essential for host defense against viral invasion. This recognition represents a fundamental step in early responses to viral threats, thereby containing the proliferation of the virus within the infected organism. In β-coronavirus recognition, multiple Toll-like receptors (TLRs) are involved. Specifically, TLR7 recognizes coronaviruses such as SARS-CoV, MERS-CoV, and murine hepatitis virus (Khanmohammadi and Rezaei 2021). In contrast, TLR2 predominantly recognizes herpes simplex virus (HSV-1). The RNA sensor RIG-I recognizes intracellular viral RNA, in which combination with TLR- and RIG-I-like receptor (RLR)-mediated pathways, stimulates transcription of IFN-inducible genes in both infected host cells and adjacent uninfected cells (Rehwinkel and Gack 2020). This process results in the production of type 1 IFNs and the establishment of an antiviral state. In addition, certain PRRs, such as AIM2 and NLRP3, contribute to the assembly of the multi-protein inflammasome. These complexes, comprising a sensor, an adaptor, and an effector, are critical detectors of viral infections and can initiate PANoptosis pathways to combat viral invasion (Oh and Lee 2023). Because pathogen infection releases endogenous nucleic acid that serve as triggers of PANoptosis, we summarize these triggers, supporting evidence, and related mechanisms in Table 2.

SARS-CoV-2 infection and PANoptosis
In the pathogenesis of SARS-CoV-2 infection, PANoptosis represents a critical mechanism that mediates both antiviral defense and immunopathological injury, characterized by an integrated PCD pathway. This process is triggered when viral components (e.g., RNA or proteins) are recognized by host PRRs (e.g., RIG-I, melanoma differentiation-associated protein 5 [MDA5]), potentially via activation of the JAK/STAT1/IRF1 signaling axis. Recognition of viral RNA not only induces an antiviral response mediated by type I IFNs (IFN-α/β) but also promotes synergistic activation of the inflammasome pathway, initiating early inflammatory signals(Karki et al. 2021b).

In severe COVID-19, persistence of these initial responses may escalate into a cytokine storm, characterized by massive production of pro-inflammatory mediators, including TNF-α and type II IFN (IFN-γ). Among these, TNF-α strongly activates cell death-associated molecules, such as Caspase-8 and RIPK3, upon receptor binding, whereas IFN-γ enhances the transcription of inflammatory genes primarily through the JAK-STAT pathway and lowers the threshold for cellular death signaling responses (Khanmohammadi and Rezaei 2021). These signals ultimately converge, leading to the assembly of core sensor proteins such as ZBP1 into a PANoptosome. This complex simultaneously mobilizes and activates Caspase-8, RIPK3, and Caspase-1. The coordinated activation of these molecules executes the PANoptotic cell death program. Subsequently, high-mobility group box 1 (HMGB1) and ATP are released which can be recognized by PRRs, thereby exacerbating local and systemic inflammation and contributing to tissue injury and multiple organ failure (Fig. 2, left) (Kwak et al. 2023).

Based on these mechanisms, therapeutic strategies targeting key PANoptosis regulators, such as RIPK1, RIPK3, and Caspase-8, are gaining attention as a novel approach for COVID-19 treatment strategies (Schifanella et al. 2023). Numerous preclinical studies demonstrate that inhibition of the PANoptotic pathway substantially reduces cytokine release and tissue damage, providing a theoretical basis for mitigating immunopathological injury in severe COVID-19. However, many candidate drugs remain in preclinical or early clinical development stages, and large-scale studies are needed to validate their efficacy (Schifanella et al. 2023; Khanmohammadi and Rezaei 2021; Karki et al. 2021b; Kwak et al. 2023). Deepening our understanding of the PANoptosis mechanism not only advances our knowledge of virus-host interactions but also provides new perspectives for developing interventions against coronavirus-induced immunopathology.

IAV infection and PANoptosis
During IAV infection, PANoptosis acts as a critical regulator of host immune defense mechanisms (Fig. 2, left). ZBP1, also known as DNA-dependent activator of IFN regulatory factors, detects IAV viral ribonucleoproteins through its N-terminal Zα1 and Zα2 domains, with recognition primarily dependent on Zα2. This molecular recognition event triggers ZBP1 activation, which subsequently promotes the assembly of the PANoptosome, thereby integrating and orchestrating the concurrent activation of pyroptotic, apoptotic, and necroptotic signaling cascades (Wang and Kanneganti 2021; Oh and Lee 2023; Malireddi et al. 2023; Zhang et al. 2020; Qi et al. 2023). Upon assembly and activation, the PANoptosome initiates a complex network of PCD processes. Activation of the NLRP3 inflammasome drives proteolytic cleavage and subsequent activation of Caspase-1, facilitating the maturation of pro-inflammatory cytokines IL-1β and IL-18 (Jiang et al. 2025). Simultaneously, Caspase-8 activation triggers apoptosis by recruiting downstream effector Caspases, such as Caspase-3 and Caspase-7, while the phosphorylation cascade mediated by RIPK3 and MLKL initiates necroptosis. Although the coordinated activation of multiple cell death pathways contributes to the elimination of virus-infected cells, it can also provoke excessive inflammatory responses, resulting in immunopathological damage. The massive release of inflammatory cytokines mobilizes and activates immune cells, causing tissue injury that exacerbates disease severity (Oh and Lee 2023; Malireddi et al. 2023). Notably, studies have demonstrated that ZBP1 deficiency in murine confers enhanced resistance to IAV infection, underscoring ZBP1’s critical role in mediating IAV-induced PANoptosis and regulating host antiviral defenses. These findings illuminate the complex regulatory network underlying PANoptosis during IAV infection and suggest promising therapeutic opportunities. Targeting ZBP1 signaling pathways or its downstream effectors may represent a novel strategy for modulating host immune responses against IAV infection, thereby opening new avenues for developing innovative antiviral interventions.

HSV-1 infection and PANoptosis
Humans are the only natural hosts of HSV-1. Upon entry into host cells, HSV-1 exploits host cellular resources to facilitate viral DNA replication and protein synthesis. ZBP1 recognizes HSV-1 nucleic acids and interacts with AIM2 to form a PANoptosis during HSV-1 infection. The AIM2 inflammasome, comprising ZBP1 and pyrin, is activated during HSV-1 infection. Notably, deletion of the Zα2 domain in ZBP1 suppresses HSV-1-induced cell death (Fig. 2, left). Similarly, in bone marrow-derived macrophages infected with HSV-1, the cell survival rate is increased following ZBP1 knockout, underscoring the critical role of ZBP1 in mediating PANoptosis (Lee et al. 2021). However, infected cell protein 6 (ICP6) mutants, such as those lacking the RHIM domain, are unable to suppress RIPK3, leading to the activation of the ZBP1-RIPK3-MLKL pathway (Fig. 2, right)(Guo et al. 2018). While wild-type HSV-1 maintains latent infection by inhibiting necroptosis, these mutants adopt a necroptosis-promoting strategy. Similarly, K45 RHIM mutants in murine cytomegalovirus (MCMV) are unable to suppress RIPK3, resulting in necroptosis of host cells via the ZBP1-RIPK3-MLKL pathway, which facilitates the release of viral particles (Fig. 2, right) (Upton et al. 2010).

Fungal infection-mediated PANoptosis
Candida albicans is a common fungal pathogen responsible for systemic fungal infections. During infection, C. albicans releases or exposes nucleic acids, such as Z-RNA, which are recognized by ZBP1. ZBP1 binds to these nucleic acids via the Zα domain, initiating downstream PANoptosis signaling pathways. Upon recognition of C. albicans nucleic acids, ZBP1 interacts with RIPK1, RIPK3, and Caspase-8 to form the PANoptosome complex (Banoth et al. 2020). This activation leads to cell membrane perforation and the release of inflammatory cytokines, including IL-1β and IL-18, via the activation of Caspase-1 and GSDMD. Concurrently, PANoptosis induces PCD through the activation of Caspase-3/7, while the activation of RIPK3 and MLKL results in cell membrane rupture and the release of cellular contents (Briard et al. 2021). By integrating multiple modes of cell death, PANoptosis limits the replication and spread of C. albicans, enhancing host antifungal immunity. It also contributes to pathogen clearance through the release of inflammatory factors; however, excessive PANoptosis can trigger heightened inflammation and tissue damage. Furthermore, C. albicans evades immune clearance by modulating the PANoptosis pathway, for example, through inhibition of ZBP1 or RIPK3 (Banoth et al. 2020).
Aspergillus fumigatus, a ubiquitous environmental fungus, causes invasive aspergillosis, particularly in individuals with immunocompromised conditions (Qi et al. 2023). Fungal cell wall components, such as β-glucans, are recognised by PRRs, initiating immune responses. During infection, A. fumigatus may release or expose nucleic acids, including Z-RNA, which are detected by ZBP1. ZBP1, through its Zα domain, binds to these nucleic acids, facilitating the formation of the PANoptosome complex in conjunction with RIPK1, RIPK3, and Caspase-8 (Pandeya and Kanneganti 2024). This complex subsequently activates downstream signaling pathways, culminating in the induction of PANoptosis.

Bacteria infection mediated PANoptosis
Unlike infections with C. albicans or A. fumigatus, Yersinia species induce a form of PANoptosis that is ZBP1-independent but RIPK1-dependent. Yersinia promotes the assembly of RIPK1-containing PANoptosome, which regulates all three branches of PANoptosis. RIPK1 activation is essential for Yersinia-induced pyroptosis and apoptosis, as well as for mounting an effective host response. Evidence of PANoptosis during Yersinia includes the coordinated activation of proteins involved in pyroptotic, apoptotic, and necroptotic pathways (Fig. 3). Notably, RIPK1 depletion attenuates Yersinia-induced pyroptosis and apoptosis while augmenting necroptosis (Malireddi et al. 2020b).

PANoptosis and disease occurrence and progression
PANoptosis is a novel PCD mechanism that integrates the key features of pyroptosis, apoptosis, and necroptosis. Its regulatory network is complex and has been closely implicated in the pathogenesis and progression of a broad spectrum of diseases (Graphic abstract).

Renal damage

AKI
AKI is a common critical condition in clinical practice that substantially increases patient mortality and may progress to chronic kidney disease (CKD). In severe cases, it can lead to multi-system complications and can be life-threatening. Accumulating evidence indicates that PANoptosis plays an instrumental role in AKI pathogenesis and progression (Chen et al. 2025). AKI can be triggered by various stimuli, including sepsis, ischemia–reperfusion (I/R), cisplatin, hemolysis/hemoglobin. AKI frequently occurs as a complication of sepsis. Research demonstrates that EIF2AK2 directly upregulates AIM2, thereby activating PANoptosis during sepsis-associated acute kidney injury, which exacerbates cell death, tissue damage, and organ damage. Notably, AIM2 depletion alleviates sepsis-induced AKI, highlighting its critical role in disease pathogenesis (Wei et al. 2024). Necrostatin-1 exerts renal protective effects in a mouse model of non-heart-beating donor transplantation by attenuating I/R-induced AKI through RIPK1-mediated suppression of PANoptosis pathways (Dokur et al. 2024). Additionally, 3,4-methylenedioxy-β-nitrostyrene (MNS) protects the kidney against I/R injury by inhibiting the NLRP3 protein, thereby reducing PANoptosis (Uysal et al. 2022). Cisplatin-induced AKI involves complex molecular mechanisms that converge on PANoptosis activation, triggering significant inflammatory responses that promote AKI pathogenesis and progression (Lin et al. 2024a). Studies further demonstrate that under hemoglobin combined with TNF-α, NLRP12 drives inflammasome activation and PANoptosome complex formation, thereby promoting cell death and inflammation. Experimental evidence from murine models shows that NLRP12 deficiency markedly reduces AKI incidence and mortality in hemorrhagic disorders. These findings highlight NLRP12 and its downstream signaling components as promising therapeutic targets for hemolysis-induced and inflammation-associated renal injury. Notably, in hypoglycemic models, NLRP12 ablation conferred protection against lethal AKI, further substantiating its mechanistic role in AKI pathogenesis (Sundaram et al. 2023).

CKD
CKD is a clinical syndrome characterized by persistent abnormalities in kidney structure or function lasting more than 3 months, arising from diverse etiologies. The progression of CKD is often triggered by a sustained inflammatory environment following initial injury. Severe burns, for example, can trigger a systemic inflammatory response that contributes to the development of CKD (Yang et al. 2025). Recent studies have demonstrated that the CKD pathogenesis involves multiple PCD pathways, including classical apoptosis, necroptosis, pyroptosis, and ferroptosis. Emerging evidence indicates the pivotal function of PANoptosis in the pathogenesis and progression of CKD (Zhang et al. 2024). These cell death mechanisms collectively induce renal parenchymal cell injury, inflammatory activation, and fibrosis, thereby exacerbating CKD. The prevalence of CKD is relatively high in burn patients following discharge. Under these conditions, studies have demonstrated that severe burns activate PANoptosis via an inflammation-mediated Caspase-dependent pathway, leading to renal injury in mice. Notably, in CKD models, the severity of this renal injury is markedly exacerbated (Yang et al. 2025).

Drug-induced nephropathy
The excessive intake of aristolochic acid in the plants is a primary contributor of aristolochic acid nephropathy (AAN). Histone deacetylases constitute a crucial class of epigenetic regulators that modulate gene expression and protein function by removing acetyl groups from acetylated modified proteins, thereby playing a pivotal role in the progress of AAN (Liu 2021). A research team demonstrated that romidepsin (FK228/depsipeptide), a specific histone deacetylase inhibitor, effectively suppresses AAN renal injury by inhibiting renal tubular epithelial cell PANoptosis. Additionally, proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) plays a critical function in AAN and AKI. Kidney-specific PSTPIP2 knock-in has been shown to suppress PANoptosis activation, thereby exerting protective effects in renal pathologies (Xu et al. 2024).

Triptolide, a bioactive diterpenoid compound derived from Tripterygium wilfordii Hook F., exhibits multifaceted pharmacological properties, including immunosuppressive, anti-tumor as well as anti-inflammatory activities. However, its clinical application is limited by a concerning profile of toxic side effects. Triptolide induces PANoptosis through ROS generation and mitochondrial dysfunction. Studies demonstrate that triptolide potently activates systemic inflammatory responses and upregulates PANoptosis-related markers, including ZBP1, RIPK3, and GSDMD, ultimately leading to renal and hepatic tissue damage (Zhang et al. 2023). Moreover, the widely used herbicide atrazine (ATR) enters and persists in water and soil, and has been implicated in causing kidney damage. Recent studies reveal that lycopene stabilizes mitochondrial DNA (mtDNA) through specific binding to the Sam50/PHB1 complex, thereby effectively suppressing ATR-induced STING-dependent PANoptosis activation in renal tissues (Yi et al. 2024).

Cardiovascular diseases

DOX-induced cardiomyopathy
Doxorubicin is a broad-spectrum cornerstone chemotherapeutic agent, primarily used for the treatment of solid tumors (Kong et al. 2022). However, its clinical use is significantly limited by cardiotoxicity, which can be life-threatening and manifests as cardiac dilation and heart failure (Kong et al. 2022; Wu et al. 2023). Recent evidence indicates that regulation of PANoptosis is associated with the onset and progression of DOX-induced cardiomyopathy (Bi et al. 2022). Experimental studies demonstrate that FUN14 domain-containing 1 (FUNDC1) mitigates DOX cardiotoxicity and mitochondrial damage by regulating PANoptosis in cardiomyocytes. Mechanically, FUNDC1 protects mtDNA from damage and cytoplasmic release by directly binding and recruiting mitochondrial Tu translation elongation factor (TUFM), thereby preventing PANoptosome formation and PANoptosis during DOX treatment. These insights provide guidance for improving the clinical application of DOX (Bi et al. 2022).

Myocardial infarction (MI)
MI is a life-threatening condition caused by coronary artery obstruction, leading to oxygen deprivation, nutrient loss, and cardiomyocyte death. Cardiovascular diseases remain the leading cause of mortality worldwide (Salari et al. 2023). Xian-Ling-Gu-Bao (XLGB) capsule, a traditional herbal formulation rich in flavonoids, terpenes, and phenylpropanoids, has demonstrated diverse therapeutic properties. Its primary compounds directly interact with NLRP3/Caspase-3/RIPK1, protecting the myocardium from MI-induced damage by inhibiting PANoptosis, and thus represent a potential therapeutic strategy for MI treatment (Wu et al. 2024).

Myocardial I/R
Myocardial I/R injury frequently occurs following adverse cardiovascular events, such as ischemic heart disease or cardiac arrest resuscitation. Paradoxically, abrupt restoration of blood flow exacerbates damage to previously ischemic myocardium (Xiang et al. 2024). Studies indicate that the expression of core PANoptosome protein exhibits time-dependent upregulation during myocardial I/R process, suggesting close association between PANoptosis and myocardial I/R injury. In addition, Piezo1, a novel cardiac mechanosensor, may exacerbate I/R injury by activating Caspase-8-mediated PANoptosis in cardiomyocytes. Notably, pharmacological inhibition of Piezo1 by GsMTx4 distinctly improved contractile dysfunction, reduced infarct size, and suppressed apoptosis, oxidative stress, and inflammatory responses in murine models, providing critical evidence for the development of therapeutics targeting Piezo1 to treat myocardial injury (Li et al. 2024). Additionally, ZBP1 has been identified as a key regulator of PANoptosis during myocardial I/R injury. Phloretin-hexose conjugate (PHC) exerts cardioprotective effects by targeting and inhibiting ZBP1 and its downstream pathways, providing a potential theoretical basis for clinical interventions (Cui et al. 2024a).

Nervous system diseases

Alzheimer’s disease (AD)
AD is one of the most prevalent forms of dementia worldwide (Dumurgier and Tzourio 2020). Currently, there is no conclusive evidence indicating that genetic alterations are the primary or most critical determinants of its development (Twarowski and Herbet 2023; Qiu et al. 2009). Inflammatory processes play a key role in the progression of AD. Multiple cell types, including astrocytes and microglia, as well as cytokines and chemokines, collectively contribute to and trigger neuroinflammation. This inflammatory milieu disrupts the neuronal microenvironment, leading to neuronal damage that promotes oxidative stress or induces apoptosis, ultimately resulting in the manifestation of AD-related symptoms (Twarowski and Herbet 2023; Newcombe et al. 2018). Bioinformatics analyses have identified key PANoptosis genes in patients with AD, and their mRNA expression level was validated in AD transgenic mice. Notably, in follicular helper T (Tfh) cells derived from high-PANscore AD patients, GSDMD and MLKL expression levels were negative correlated (Zhang and Dai 2024). These findings suggest that the pathophysiological pathways of AD are associated with PANoptosis, providing new insights for the development of therapeutic strategies.

Spinal cord ischemia–reperfusion injury(SCIRI)
SCIRI is a severe complication of thoracoabdominal aortic aneurysm surgery and endovascular aortic repair procedures. Among more than 3,000 abdominal aortic surgeries, the incidence of postoperative spinal cord ischemia was 0.25% (Tural et al. 2021). SCIRI may also result from spinal trauma, degenerative changes, or tumors, often leading to paraplegia and permanent loss of motor function (Sueda and Takahashi 2018). Experimental studies have demonstrated that treatment with the sustained-release hydrogen sulfide (H₂S) donor GYY4137 reduces Nissl body loss following SCIRI and improves functional outcomes as assessed by the Baso-Bittig-Bresnahan score. H₂S downregulates key PANoptosis related proteins, decreases the number of TUNEL-positive cells and cleaved Caspase-3-positive cells (Xie et al. 2024). By inhibiting hyperactivated microglia-mediated PANoptotic apoptosis and neuroinflammation, H₂S mitigates spinal neuron loss, underscoring significant promise to its development as a therapy for SCIRI (Xie et al. 2024).

Glaucoma
Glaucoma comprises a group of progressive optic nerve diseases, characterized by degeneration of retinal ganglion cells (RGCs) and subsequent alterations in the optic nerve head. The loss of RGCs is primarily associated with elevated intraocular pressure. Currently, intraocular pressure reduction remains the only evidence-based therapeutic approach (Weinreb et al. 2014). Emerging evidence indicates that suppression of dynamin-related protein 1 (Drp1) modulates PANoptosis in RGCs by regulating Caspase-3-mediated, NLRP3-mediated, and RIPK-mediated pathways in models of pathologically elevated intraocular pressure. Targeting the ERK1/2-Drp1-ROS signaling axis may represent a promising therapeutic strategy for mitigating intraocular pressure elevation(Zeng et al. 2023). Additionally, melatonin has been shown to suppress the expression of NLRP3 (Arioz et al. 2019), ASC, cleaved Caspase-1, GSDMD, as well as its cleaved form, while concurrently reducing the population of cells co-expressing ionized calcium-binding adapter molecule 1 (Iba1) and IL-1β. Collectively, these findings indicate that melatonin preserves retinal structural integrity, prevents functional impairment following acute ocular hypertension (AOH), and confers neuroprotection by inhibiting PANoptosis in retinal tissue subjected to AOH (Ye et al. 2022).

Ocular diseases

HSV-1-induced keratitis (HSK)
HSV-1 infection can lead to keratitis, which in severe cases may result in blindness. Evidence suggests that HSV-1 activates signaling pathways associated with apoptosis, pyroptosis, and necroptosis, indicating the occurrence of PANoptosis (Guo et al. 2022). Deletion of AIM2 and ZBP1, which act as regulators and sensors, substantially reduced the expression of key markers associated with these cell death pathways. Consequently, apoptosis, pyroptosis, and necroptosis were inhibited, compromising host defense and leading to mortality in mice following HSV-1 infection (Lee et al. 2021).

Diabetic retinopathy (DR)
DR is a common microvascular complication of diabetes, affecting approximately one-third of individuals with diabetes (Cheung et al. 2010). Emerging evidence has demonstrated a strong association between DR and PANoptosis. Chronic hyperglycemia induces oxidative stress and inflammatory factors (Roy et al. 2017). Six PANoptosis-related hub genes, including brain expressed X-linked 2 (BEX2), Caspase-2, cluster of differentiation 36 (CD36), fatty acid synthase (FASN), oncostatin M receptor, and phospholipid scramblase 3(PLSCR3), have been identified as potential biomarkers through machine learning algorithm in DR. Experimental validation revealed that knockdown of FASN and PLSCR3 alters the behavior of human umbilical vein endothelial cells (HUVECs) (Chen et al. 2024). Furthermore, administration of Dickkopf-related protein 1 (DKK1) effectively suppresses PANoptosis in the retinal tissues of streptozotocin (STZ)-induced diabetic rats. This suppression is primarily achieved through the inhibition of key markers such as cleaved GSDMD, Caspase-3, and RIPK3, leading to the alleviation of pyroptosis, apoptosis, and necroptosis(Xu et al. 2022). Additionally, DKK1 treatment enhances the physiological function of the retina in STZ-induced diabetic rats, accompanied by improvements in retinal structure (Xu et al. 2022). Collectively, these findings represent a paradigm shift in DR management, from conventional vascular protection to a precise regulation of cell death.

Retinal I/R injury
I/R injury in retinal tissues is a key major contributor to glaucomatous neurodegeneration, potentially leading to RGC death and vision loss. Studies demonstrate the presence of apoptosis, pyroptosis, and necroptosis signaling molecules in retinal I/R injury in mice, suggesting that PANoptosis-like cell death may occur in retinal neurons under conditions of acute intraocular pressure elevation. Using an in vitro oxygen–glucose deprivation/reperfusion (OGD/R) model with R28 cells and an in vivo acute intraocular pressure mode l(Yan et al. 2023), researchers observed significant upregulation of the apoptotic marker Caspase-3, the pyroptosis marker GSDMD, and the necroptosis marker MLKL in RGCs. Additionally, different combinations of apoptosis, pyroptosis, and necroptosis inhibitors exhibited variable protective effects on R28 cells following OGD/R. Notably, the use of one or two PCD inhibitors alone did not prevent OGD/R-induced RGC death, whereas the combination of all three PCD inhibitors conferred the greatest protection for R28 cells (Yan et al. 2023). These findings suggest that acute intraocular hypertension may be associated with PANoptosis.

Fungal keratitis (FK)
FK is a prevalent and severe ocular infection that triggers a complex host immune response, paradoxically contributing to corneal tissue destruction while simultaneously eliminating the fungal pathogen (Ratitong and Pearlman 2021; Niu et al. 2020). This dual role of immune activation critically modulates the clinical course of FK, influencing disease severity and visual outcomes. Experimental evidence demonstrates that following A. fumigatus infection, the PANoptosis pathway, mediated by AIM2, pyrin, and ZBP1, is activated in murine corneal tissues (Lee et al. 2021; Xu et al. 2023). Notably, this PANoptosis activation precipitates the release of substantial pro-inflammatory cytokines, including IFN-γ, IL-1β, IL-6, IL-17A, and TNF-α, which are implicated in the immunopathological progression of FK. The observed upregulation of these cytokines post-infection correlates with exaggerated corneal inflammation, establishing a mechanistic link between PANoptosis activation and disease pathogenesis (Xu et al. 2023). These findings underscore the therapeutic potential of targeting PANoptosis regulation, offering a new strategy to mitigate excessive inflammation in patients with FK and highlighting broader implications for the management of infectious diseases.

PANoptosis and tumors
PANoptosis inhibits tumor growth to a certain extent in tumor cells (Cui et al. 2024b). Recent research indicates that PANoptosis is intricately involved in tumor initiation, invasion, and metastasis. This section reviews the critical roles of PANoptosis in tumor development and cancer therapy (Pu et al. 2025) (Table 3).

PANoptosis and gastric cancer
In exploring the association between PANoptosis and cancer, researchers have analyzed diverse PANoptosis patterns and constructed a PANscore system to quantify the PANoptosis characteristics of individual patients with gastric cancer (Christgen et al. 2020). Studies across multiple independent patient cohorts have validated the reliability of the PANscore in predicting prognosis and evaluating the efficacy of immunotherapy. A PANoptosis-related prognostic signature (PANscore) was developed through regression analysis of gene expression data, resulting in a five-gene model. The PANscore for each patient is calculated as: PANscore = (0.253 × IL1A) + (−0.487 × DFFB) + (0.616 × UNC5B) + (−0.383 × TICAM1) + (−0.392 × FASLG), with higher scores indicating a higher risk profile (Pan et al. 2022). Pan cancer analysis further revealed significant correlations: patients with higher PAN scores often exhibit decreased expression of immune checkpoints, elevated levels of transforming growth factor-β, intensified infiltration of cancer-associated fibroblasts (CAFs), and increased aggregation of M2 macrophages. Conversely, patient populations with lower PAN scores generally respond better to immunotherapy and exhibit more favorable clinical outcomes (Pan et al. 2022).
Beyond its established roles in DNA repair and RNA biology, Y-box binding protein 1 (YBX1), plays dual roles in cancer, driving proliferation in gastric cancer while restraining PANoptosis in pancreatic cells. This functional duality is modulated by a specific post-translational circuit: interaction with PPM1B promotes dephosphorylation at Ser314 of YBX1, which in turn blocks USP10-dependent deubiquitination. The resulting instability and decreased abundance of YBX1 fine-tune its output in both cell proliferation and PANoptosis (Lin et al. 2024b).

IRF1-mediated PANoptosis and colorectal cancer
IRF1 has been identified as a key mediator of PANoptosis that suppresses colorectal cancer development. Studies indicate that mice genetically deficient in IRF1 exhibit heightened susceptibility to colorectal tumorigenesis. In contrast, IRF1 actively inhibits tumor formation in a naturally occurring mouse model of colorectal cancer. The reduced cell death observed in the colons of IRF1-deficient mice is attributed to impaired PANoptosis. Notably, the influence of IRF1 on the colon appears specific to PANoptosis and does not extend to the regulation of inflammation or the inflammasome. Collectively, these findings establish IRF1 as a pivotal upstream regulator that promotes cell death via PANoptosis in colitis-associated tumorigenesis (Karki et al. 2020; Thuya et al. 2025).

PANoptosis and breast cancer
Emerging evidence highlights the role of CAFs in modulating PANoptosis within the breast TME. Specifically, IL-6 derived from CAFs upregulates the expression of cell death-related molecules through the JAK-STAT3 signaling pathway, synergizing with additional death signals such as TNF-α to induce PANoptotic cell death (Hu et al. 2021).
This induction of PANoptosis contributes to an anti-tumor response. Growing evidence indicates that PANoptosis, a novel PCD mechanism, plays a critical role in breast cancer progression. Systematic analysis of gene expression profiles in breast cancer reveals that elevated PANoptosis-related genes confer protective effects against tumor progression. Furthermore, a PANoptosis-based prognostic model has been developed and validated, demonstrating significant clinical utility for predicting survival outcomes in patients with breast cancer (He et al. 2023). Among PANoptosis-associated prognostics, radixin exhibited the highest hazard ratio and was notably expressed in arterial endothelial cells. Radixin actively participates in diverse biological processes, including immune response and cell proliferation, underscoring its diverse functional roles (He et al. 2023).

PANoptosis and prostate cancer
Genotoxic therapies, such as radiotherapy, induce DNA double-strand breaks that are recognized by ZBP1 through its affinity for severe genomic lesions or exposed nucleic acid structures. Upon activation, ZBP1 serves as a central scaffold, recruiting and assembling key components, including RIPK1, RIPK3, Caspase-8, and NLRP3 inflammasome subunits, into the multi-protein complex PANoptosome. Formation of this complex irreversibly initiates PANoptosis, effectively eliminating prostate cancer cells. This ZBP1-dependent pathway represents a pivotal mechanism underlying the anti-tumor effects of genotoxic treatments such as radiotherapy (Yang et al. 2021; Wang et al. 2024). However, despite the effectiveness of such genotoxic approaches, prostate cancer remains challenging to treat with immunotherapy due to its immunosuppressive TME.

Characteristics of prostate cancer include low antigen expression, weak tumor suppression, and limited immune cell entry (He et al. 2022). Consequently, certain prostate cancer subtypes exhibit poor responsiveness to immunotherapy, contributing to drug resistance, tumor recurrence, metastasis, and poor patient prognosis. These challenges underscore the need for novel therapeutic strategies, with a particular focus on targeting cell death pathways (Ocansey et al. 2024). Researchers have established a PANoptosis signature by analyzing The Cancer Genome Atlas (TCGA) data from 52 patients with biochemical recurrence. The signature score, calculated by averaging the enrichment scores of PANoptosis-related genes, enabled accurate predictions of patient prognosis and immunotherapy response (Yi et al. 2023). Patients were stratified into high- and low-score cohorts to further elucidate the molecular and immune mechanisms associated with this signature. Patients in the high-score cohorts demonstrated significantly longer survival and a more enhanced response to immunotherapy (Yi et al. 2023). Additionally, this cohort exhibited higher mutation frequencies and increased enrichment in PANoptosis and tumor hallmark pathways. Mechanistic studies revealed that PANoptosis signaling effectively activates anti-tumor immune responses, promotes immune cell infiltration into tumor tissues, and modulates immune checkpoint expression, thereby remodeling the TME and converting "cold tumors" into immunologically active states (Yi et al. 2023). In summary, the PANoptosis signaling pathway constitutes a critical prognostic indicator in prostate cancer and substantially influences clinical outcomes among patients with prostate cancer.

PANoptosis and other cancers
Various tumor types demonstrate a close relationship with PANoptosis. Sulconazole is an allylamine-class antifungal agent mainly used to cutaneous fungal infections. Interestingly, sulconazole exhibits notable anticancer effects by inducing PANoptosis in esophageal cancer cells. In terms of mechanism, sulconazole triggers mitochondrial oxidative stress and inhibits glycolysis by downregulating hexokinases and suppressing several key oncogenic signaling pathways. Furthermore, sulconazole the efficacy of radiotherapy by amplifying mitochondrial oxidative stress, positioning it as a promising anticancer candidate with potential clinical application in esophageal cancer (Liu et al. 2023). PiR-27222 promotes Wilms’ tumor 1-associating protein (WTAP) expression by deubiquitinating and stabilizing eukaryotic translation initiation factor 4B (eIF4B), thereby preventing cellular PANoptosis through suppression of Caspase-8 in a WTAP-mediated N⁶-methyladenosine (m6A)-dependent manner. PiR-27222 mediates PM2.5-induced resistance to cellular PANoptosis in lung cancer through WTAP/m6A, thereby promoting tumor progression (Ma et al. 2024). Through bioinformatic analysis, Li et al. firstly revealed the crucial role of PANoptosis in thyroid cancer and constructed an 8-gene diagnostic signature that demonstrated excellent diagnostic performance in both training and validation cohorts. They found that PANoptosis likely contributes to thyroid cancer progression by modulating the immune system, particularly through macrophage infiltration and the TNF signaling pathway. These findings not only provide new insights into the pathogenesis of thyroid cancer but also identify potential targets for developing novel CAR-macrophage-based immunotherapies (Li and Wu 2024). Collectively, these studies highlight the broad relevance of PANoptosis across multiple tumor types and underscore its potential as a therapeutic target.

Summary and prospect
Although individual modes of PCD, such as pyroptosis, apoptosis, and necroptosis, have demonstrated potential therapeutic value in a range of diseases, including infectious, oncological, and neurological disorders, they also exhibit a dual nature. By extension, PANoptosis likely plays a pivotal role in diverse pathological conditions. Targeted modulation of PANoptosis, tailored to the specific microenvironment, holds considerable promise as an effective therapeutic strategy. Notably, compared with the independent regulation of pyroptosis, apoptosis, and necroptosis, strategies aimed at controlling PANoptosis may prove simpler and yield more pronounced therapeutic effects. Current research on PANoptosis has not yet clarified whether this form of cell death occurs within individual cells or across cell populations. While this question may be challenging to resolve, it remains a critical issue for the field.
Despite the promising therapeutic prospects of PANoptosis in treating various diseases, several challenges persist. The precise mechanisms governing PANoptosis remain incompletely understood, and the specific functions of the proteins comprising the PANoptosome require further investigation. Moreover, the relationship between PANoptosis and other therapeutic modalities, such as radiotherapy, chemotherapy, and immunotherapy, has yet to be fully elucidated. The integration of PANoptosis-targeted interventions into conventional treatment regimens has the potential to pave the way for individualized and precision-based therapeutic strategies, particularly in oncology. In conclusion, as an essential and closely interconnected form of PCD, PANoptosis plays a critical role in the pathogenesis of numerous diseases, including infections, cancer, neurodegenerative diseases, and inflammatory conditions. Further in-depth exploration of its molecular and regulatory mechanisms is expected to reveal novel therapeutic avenues and strategies, ultimately advancing clinical management across diverse disease contexts.

Abbreviations
ADAlzheimer’s Disease
ADAR1Adenosine Deaminase Acting on RNA 1
AIM2Absent In Melanoma 2
AKIAcute Kidney Injury
ASC Apoptosis-Associated Speck-like Protein Containing a CARD

ATRAtrazine
CKDChronic Kidney Disease
DAMPDamage-Associated Molecular Pattern
DOXDoxorubicin
DRDiabetic Retinopathy
FKFungal Keratitis
GSDMDGasdermin D
HSV-1Herpes Simplex Virus Type 1
IAVInfluenza A Virus
IFNInterferon
IRF1Interferon Regulatory Factor 1
JAK/STATJanus Kinase/Signal Transducer and Activator of Transcription Janus
MLKLMixed Lineage Kinase Domain-Like
MNS3,4-methylenedioxy-β-nitrostyrene
NLRP3 NLR Family Pyrin Domain Containing 3

NLRP12NLR Family Pyrin Domain Containing 12
PAMPPathogen-Associated Molecular Pattern
PCDProgrammed Cell Death
PRRPattern Recognition Receptor
RGCRetinal Ganglion Cell
RHIMRIP Homotypic Interaction Motif
RIPK1/3 Receptor-Interacting Protein Kinase 1/3

SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2

SCIRI Spinal Cord Ischemia-Reperfusion Injury

TLRToll-Like Receptor
TMETumor Microenvironment
TNF-αTumor Necrosis Factor Alpha
ZBP1Z-DNA Binding Protein 1