The PANoptosome constitutes a regulatory platform formed by inflammasomes associated with apoptosis, pyroptosis and necroptotic cell death (37), simultaneously mediating the occurrence of PANoptosis. The activation and assembly of the PANoptosome are crucial for PANoptosis. Its assembly domain comprises three components: i) Recognition of pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and sensors (for example, ZBP1, AIM2, NLRP3 and NLRP12); ii) sensor-adapter complex formation [e.g., apoptosis-associated Speck-like protein containing a CARD (ASC) and Fas-associated death domain protein (FADD)]; and iii) recruitment of catalytic effectors (such as RIPK3, RIPK1, CASP-1, CASP-8 and NLRP3) (14). Variations in specific sensors activate distinct PANoptosome assemblies. There are currently four known primary types of PANoptosomes: ZBP1, AIM2, RIPK1 and NLRP12 PANoptosomes (38). Furthermore, studies have indicated that activation of the gastric epithelial cell pattern recognition receptor (PRR) NLR family CARD domain containing 4 (NLRC4) promotes the activation of factors including ASC, NLRP3, CASP-8, RIPK1, RIPK3 and ZBP1, Caspase-1 and FADD (39), thereby inducing inflammasome assembly.

The PANoptosome, which functions as a molecular scaffold, is driven primarily by CASPs and RIPKs, subsequently promoting the activation of downstream executioner molecules. It triggers pyroptosis via the NLRP3-ASC-CASP-1-gasdermin (GSDM)D pathway (40,41), whereas CASP-8 activates the effector CASPs CASP-3/6/7 to cleave BID and induce its mitochondrial translocation, inducing cytochrome c release (42,43), and concurrently activating RIPK1 and RIPK3 to induce mixed lineage kinase domain-like protein (MLKL) phosphorylation, thereby mediating necroptosis (44). Given the close association of PANoptosis with inflammatory diseases and tumorigenesis, the PANoptosome and its assembly may serve pivotal roles in these processes. Consequently, the PANoptosome is a key therapeutic target.

Apoptosis is a noninflammatory form of cell death characterized by intact cell membranes, whereas necroptosis and pyroptosis represent soluble and inflammatory forms of cell death (2), respectively. Complex signal crosstalk occurs among these three pathways and serves a notable role in disease progression (45,46). CASP-8 serves as a pivotal factor in signal crosstalk between apoptosis, pyroptosis and necroptosis, and can inhibit RIPK3- and MLKL-mediated necroptosis (47). However, CASP-8 has distinct functions in different states. In its activated form, CASP-8 mediates pyroptosis by cleaving GSDMD and GSDME via CASP-1 and CASP-3, respectively. Inactivated CASP-8 promotes ASC (inflammasome component) and CASP-1 activation (48), facilitating pyroptosis and the secretion of proinflammatory cytokines (such as IL-1β and IL-18). CASP-1, in turn, induces apoptosis via the BID-CASP-9-CASP-3 axis (BID being a BCL-2 family member) or by directly activating CASP-6 and CASP-3 (41,49,50). However, in the presence of inactivated CASP-8, TNF-α activates RIPK1 to bind to CASP-8, shifting the apoptotic pathway toward necroptosis via the RIPK1-RIPK3-MLKL axis (51,52). Stimulation of Fas, TNF-related apoptosis-inducing ligand receptor, Toll-like receptor (TLR)3 and TLR4 also induces necroptosis (53). The concept of PANoptosis was initially proposed to offer mutually alternative and complementary pathways for PCD, thus expanding the understanding of cell death and the pathogenesis of inflammatory diseases, potentially aiding disease diagnosis, treatment and prevention.

A major challenge in PANoptosis research is to distinguish PANoptosome-dependent integrated PANoptosis from the parallel, independent activation of apoptosis, pyroptosis and necroptosis. To ensure conceptual rigor and avoid overinterpretation in gastric mucosal studies, the following clear and practical experimental criteria are proposed:

i) Molecular criterion: Direct demonstration of PANoptosome assembly. The gold standard for PANoptosis is the formation of a physical PANoptosome complex. This requires evidence such as co-immunoprecipitation, proximity ligation assay (54) or immunofluorescence colocalization (55) confirming the interaction of core sensors (ZBP1/AIM2/RIPK1/NLRP12) (56), adaptors (ASC/FADD) and effectors (RIPK3, CASP-1, CASP-8) in gastric cells or tissues (37).

ii) Functional criterion: Simultaneous blockade of all three death pathways. Inhibition or knockout of a core PANoptosome component [e.g., ZBP1, AIM2 or IFN regulatory factor 1 (IRF1)] (29,57) must simultaneously suppress apoptosis, pyroptosis and necroptosis. By contrast, inhibition of a single pathway (such as CASP-3, GSDMD or MLKL) should only partially reduce cell death, indicating PANoptosis rather than parallel activation.

iii) Phenotypic criterion: Concurrent biochemical and morphological features. PANoptotic cells simultaneously display (54): Apoptotic markers, cleaved CASP-3/7 and PARP; pyroptotic markers, cleaved GSDMD/GSDME; and necroptotic markers: Phosphorylated (p)-RIPK3 and p-MLKL. They should also exhibit a combined morphology: Cell shrinkage, nuclear fragmentation, membrane swelling and rupture (58).

Notably, the mere coexistence of apoptotic, pyroptotic and necroptotic markers does not confirm PANoptosis. Only when cell death is driven by a unified PANoptosome complex can it be defined as PANoptosis. This distinction is critical for mechanistic studies in gastric mucosal diseases.

Common diseases causing acute gastric mucosal injury include acute gastritis and gastric ulceration. Previous studies have revealed that their pathogenesis is associated with PANoptosis (Fig. 1) (60,61). Previous studies have indicated that the gastric mucosa, under various stimuli, such as heavy alcohol consumption, nonsteroidal anti-inflammatory drug use and Helicobacter pylori (HP) infection, exhibits mitochondrial damage and dysfunction. This leads to increased release of DAMPs, including mitochondrial reactive oxygen species (mROS) and mitochondrial DNA (mtDNA). Upon recognition by TLRs in gastric epithelial cells, mtDNA binds to ZBP1 and AIM2, regulating inflammation via the TANK-binding kinase 1 (TBK1)/IRF pathway (38,62,63). This process stimulates the activation of multiple inflammasomes, including NLRP3, NLRP12 and NLRC4 (60,64), which are key regulatory factors in PANoptosis in gastric epithelial cells. For example, ethanol activates the NLRP3 inflammasome via the nuclear factor erythroid 2-related factor 2 (NRF2)-heme oxygenase-1 (HO-1)-NF-κB signaling pathway (65), which combines with calcium ion channel proteins to promote the release of mtDNA and mROS. The release of mtDNA and mROS activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway, upregulating the expression of ZBP1 and AIM2 and facilitating their binding (62,66). Concurrently, it recruits RIPK1, RIPK3, CASP-1 and CASP-8 in gastric glandular parietal cells (33,64). These proteins participate in the assembly of the AIM2-ZBP1-PANoptosome complex, thereby inducing PANoptosis. Activation of PANoptosis leads to the excessive release of proinflammatory cytokines, including IL-1β, IL-18 and TNF-α, amplifying the immune response, and exacerbating the onset and progression of acute gastric mucosal injury.

Notably, substantial amounts of high mobility group box 1 (HMGB1) released during gastric mucosal injury can bind to mtDNA (66), thereby limiting excessive AIM2 activation and competitively inhibiting PANoptosis. However, as a DAMP, HMGB1 binds to TLR4 and receptor for advanced glycation end products (61), activating the NF-κB pathway to increase TNF-α production. This subsequently induces PANoptosis in gastric mucosal cells, thereby contributing to the development and progression of gastric ulcers. Thus, in acute gastric mucosal injury, the complex regulation of local gastric immunity leads to excessive activation of PANoptosis during the mucosal immune response, promoting the progression of mucosal damage. Moderate activation of generalized apoptosis may be a therapeutic target for gastric mucosal injury diseases.

Infectious diseases of gastric epithelial cells include viral gastritis, bacterial gastritis and fungal gastritis, among others. Numerous studies have indicated that during the initial phase of infection by various pathogens, including viruses, bacteria and fungi, PAMPs can limit intracellular pathogen replication by initiating PANoptosis (38,67,68), a form of PCD, thereby facilitating host recovery. However, persistent infection leads to excessive activation of PANoptosis, resulting in the massive release of inflammatory cytokines; this triggers an inflammatory storm, exacerbating damage to gastric mucosal tissue (Fig. 2).

PANoptosis was initially identified and proposed in the context of influenza A virus infection (38). In addition, gastric herpes simplex virus type 1 (HSV-1) infection is regulated by PANoptosis. HSV-1 is a double-stranded DNA (dsDNA) virus (67), and when it invades the gastric mucosal epithelium, it promotes the activation of AIM2, pyrin, ZBP1, ASC, RIPK3, RIPK1, FADD, CASP-1 and CASP-8 to assemble AIM2-PANoptosomes and ZBP1-PANoptosomes (16), thereby mediating PANoptosis to inhibit viral replication. However, when viral infection stimulates excessive activation of immune cells and massive cytokine release, the release of TNF-α and IFN-γ jointly enhances PANoptosome assembly, driving PANoptosis to exacerbate damage to the gastric mucosal epithelium (38). Similarly, although no studies have yet demonstrated that the ability of the dsDNA virus Epstein-Barr virus (EBV) (68) to infect gastric epithelial cells is linked to PANoptosis, its viral structural properties suggest that this may be possible; however, direct evidence in gastric epithelial cells is lacking. EBV may potentially activate ZBP1/AIM2, but this remains to be verified in gastric models. The mechanisms underlying viral gastric mucosal infection remain incompletely understood; however, PANoptosis in early infection confers protection to a certain degree, offering novel therapeutic perspectives for viral gastritis.

HP, Francisella and Yersinia species are common pathogens involved in gastric mucosal cell bacterial infections. As PAMPs, they activate TLRs, which are primary PRRs in the gastrointestinal tract that respond to pathogenic infection. PAMPs (e.g., β-glucan, chitin, mannans and fungal nucleic acids) bind to hemoglobin, stimulating specific TLRs (TLR2 and TLR4) on the gastric mucosa to activate the NF-κB and ERK pathways (61,69). This increases the expression of IRF1, leading to the upregulation of AIM2 and NLRP12 expression (34,70). This in turn induces the assembly of AIM2-PANoptosomes and NLRP12-PANoptosomes, mediating widespread PANoptosis in immune cells and promoting inflammatory damage to the gastric mucosa. By contrast, Yersinia-induced gastritis occurs via the Yersinia outer protein J, which inhibits TGF-β activating kinase 1 (17), thereby promoting RIPK1-mediated assembly of the RIPK1-ASC-CASP-1-FADD complex, CASP-8 and FADD, leading to the formation of the RIPK1-PANoptosome and thereby inducing PANoptosis to promote the onset and progression of gastritis.

For common HP infectious gastritis, mitochondrial damage is induced through the virulence factors CagA and VacA, promoting the accumulation and release of large amounts of mtDNA and ROS, which induces PANoptosis in gastric epithelial cells, driving cell death and inflammatory responses (32). Traditional anti-HP treatments primarily focus on eradicating the pathogen and alleviating mucosal inflammation, but they cannot reverse already formed mucosal damage, chronic inflammation or infection-induced cascades of cell death (71). By contrast, inhibiting PANoptosis can directly block the vicious cycle of inflammation and cell death, more effectively alleviating mucosal damage by reducing the excessive release of IL-1β, IL-18 and TNF-α (32,72); when combined with HP eradication therapy, it may help accelerate mucosal repair and reduce the risk of inflammation-related precancerous lesions. These findings demonstrate that PANoptosis serves a role in the development of bacterial gastritis and may represent a novel therapeutic target.

Fungal infections commonly occur in immunocompromised individuals, with Candida albicans and Aspergillus species being the most prevalent causative agents of gastric mucosal fungal infections (16,28). Research has indicated that ZBP1 serves as an apical sensor for fungal infection (28). Upon infection by C. albicans or Aspergillus fumigatus, substantial amounts of PAMPs (e.g., fungal cell wall components, nucleic acids and glycans) are secreted, activating ZBP1 to promote ZBP1-PANoptosome assembly. Furthermore, another study has revealed that during Aspergillus invasion (6,73), the fungus is recognized by host cells via TLRs, specifically TLR2, TLR4, TLR9 and dectin-1. Dectin-1 specifically recognizes β-glucans in fungal cell walls (74), triggering the release of substantial PAMPs that activate the cytoplasmic sensor AIM2. This activity mediates AIM2-PANoptosome assembly, inducing PANoptosis. This pathway may underlie the pathogenesis of fungal gastritis.

In the early stages of infection by pathogens such as viruses, bacteria and fungi in the gastric mucosal epithelium, the activation of PANoptosis aids in preventing pathogen replication and invasion. However, excessive and sustained activation of PANoptosis may promote the progression of inflammation and exacerbate damage to gastric mucosal epithelial tissue. Therefore, achieving a balanced activation of PANoptosis is crucial for the early prevention of infectious diseases of the gastric mucosa. For pathogenic infection-mediated chronic mucosal inflammation and epithelial cell damage, compared with traditional anti-infective treatments, targeted inhibition of PANoptosis may block the vicious cycle of inflammation and cell death, and promote repair of the mucosal barrier.

Autoimmune gastritis occurs when the autoantigen H⁺-K⁺ adenosine triphosphatase on parietal cells is recognized by autoreactive CD4⁺ T cells (75), leading to spontaneous inflammatory infiltration and atrophy of the gastric mucosa. This suggested mechanism has been extrapolated from autoimmune disease models; direct in vivo evidence in gastric tissues is still insufficient. TNF-α and IFN-γ may act via JAK/STAT1/IRF1 (36) to drive inducible nitric oxide (NO) synthase to produce NO. This activates FADD/RIPK1/RIPK3-mediated CASP-8/Fas-associated protein ZBP1 and AIM2-PANoptosome assembly, inducing gastric epithelial cell PANoptosis to promote autoimmune gastritis. Moreover, TNF-α binds to the TNF receptor, stimulating RIPK1 to interact on CASP-8 via FADD and induce apoptosis (76). Simultaneously, RIPK1 binds to RIPK3 through the RIPK homotypic interaction motif (RHIM) domain, inducing necroptosis (77). Furthermore, activated ZBP1 promotes IL-17 secretion by CD4⁺ T helper 17 cells, which directly act on gastric parietal cells. This activates CASP-3-mediated apoptosis via the p53 and PI3K/Akt signaling pathways (78) or drives pyroptosis, thereby advancing autoimmune gastritis progression (Fig. 3).

In summary, PANoptosis may be an important regulatory factor exacerbating the progression of autoimmune gastritis, and appropriately blocking its activation represents an effective therapeutic strategy for this condition. Previous studies have confirmed that IRF1 is a key upstream regulator of PANoptosis mediated by factors including ZBP1, AIM2 and NLRP12 (70,79), and IRF1 deficiency reduces the activation of PANoptotic molecules. Conversely, mutations or loss of function in adenosine deaminase 1 generates endogenous Z-RNA, activating ZBP1-mediated PANoptosis (36). This mechanism presents a potential therapeutic target for autoimmune gastritis.

SPEM constitutes an important mucosal repair lineage capable of progressing to intestinal metaplasia, thereby promoting gastric carcinogenesis. Evidence has clearly indicated that IL-13 acts as an initiating factor in SPEM development (80), whereas IL-33 acts as an upregulating factor (81), inducing SPEM through stimulating M2 macrophage activation. Notably, SPEM development is closely associated with PANoptosis. Gastric AIM2 is produced primarily by gastric B220⁺ IgM⁺ immune cells (82). During gastric mucosal injury, elevated AIM2 expression activates ZBP1 through the sensing of endogenous dsDNA or mtDNA (83), which participate in AIM2-PANoptosome assembly to mediate gastric mucosal cell PANoptosis. Subsequently, CASP-6 is activated as a downstream component and interacts with IL-4 to promote macrophage activation via nonapoptotic pathways (84). Concurrently, IL-10 secretion inhibits M1 macrophage activation (85) while enhancing M2 macrophage activation and expression, thereby promoting the development of SPEM in the gastric mucosa (Fig. 4). However, most evidence comes from gastric injury models; direct evidence of PANoptosome assembly in SPEM-specific lineages is lacking.

Furthermore, M2 macrophage activation induces CASP-6 upregulation, the release of N-terminal GSDME, the phosphorylation of MLKL (86), and the binding of RIPK3 to the RHIM domain of ZBP1 to stimulate ZBP1-PANoptosome assembly (87), thereby increasing PANoptotic activity. However, the noninflammasome AIM2 can inhibit the progression of SPEM by restricting CD8⁺ T-lymphocyte accumulation in chronic gastritis through the suppression of CXCL16 (produced by gastric B cells) (82).

Research has revealed that the absence of GRIM-19 in parietal cell mitochondria can promote NLRP3/IL-33 activation via the ROS-NRF2-HO-1-NF-κB pathway, thereby mediating the development of SPEM (88). Following gastric mucosal injury, NLRP3 upregulation is induced, promoting M2 macrophage activation and CD8⁺ T-cell recruitment. This contributes to gastric SPEM development by increasing IFN-γ production (89). The mechanism by which NLRP3 induces M2 macrophage activation remains unclear. On the basis of these findings, it may be hypothesized that gastric mucosal injury increases NLRP3 expression, which, via the CASP-1 pathway, triggers the massive release and secretion of inflammatory cytokines. This enhances the activity of dendritic cells, neutrophils, gastric B cells and natural killer cells (90); promotes the upregulation of TNF-α and IRF1; and induces activation of the AIM2 inflammasome through guanine nucleotide-binding protein (66). Stimulation of AIM2-PANoptosome assembly mediates SPEM development. Transcriptomic analysis has further revealed that these immune cells express PANoptosis-related genes (PANoDEGs), such as IL1B, IL18, TNF, CASP1 and MLKL, indicating that the aforementioned immune cells are involved in the pathogenesis of SPEM (66). This stimulates AIM2-PANoptosome assembly, mediating SPEM via PANoptosis. Transcriptomic analysis has revealed strong associations between these immune cells and PANoDEGs (91). Furthermore, heightened inflammatory cell activity increases the secretion of the gastric mucosal injury alarmins IL-33 and HMGB1 (92). These DAMPs may activate inflammasomes such as ZBP1 and AIM2, mediating the recruitment of NLRP3, RIPK3, RIPK1 and CASP-8 to assemble PANoptosomes. This PANoptosis pathway thereby promotes SPEM progression. Current direct evidence of PANoptosome assembly in SPEM-specific epithelial cells is still lacking; therefore, PANoptosis is a potential regulatory factor in SPEM, and its core role requires further verification.

The incidence and mortality rates of malignant gastric cancer remain high, ranking fifth in cancer incidence and fourth in cancer-related mortality globally (93,94). The emergence of PANoptosis, a novel form of cell death, offers fresh therapeutic options for tumor management. In gastric cancer, AIM2 upregulation is induced (35), thereby initiating the assembly of AIM2-PANoptosomes within tumor cells. IRF1, TNF-α and IFN-γ have been demonstrated to induce PANoptosis to prevent tumorigenesis (29,95,96). As an upstream regulator of PANoptosis, IRF1 produces NO to modulate TNF-α and IFN-γ expression via the JAK/STAT1 signaling pathway (90,97). The interaction of TNF-α and IFN-γ activates GSDME, CASP-8/3/7 and MLKL phosphorylation, thereby inducing PANoptosome assembly. Furthermore, the combination of IFN with a nuclear export inhibitor (98) enhances ZBP1-PANoptosome assembly, inducing robust PANoptosis in tumor cells and inhibiting their proliferation (Fig. 5).

The therapeutic effect of cisplatin on gastric cancer cell is mediated by the activation of CASP-8/9 and downstream CASP-3/7 to induce apoptosis (99). This occurs because CASP-1 stimulates increased CASP-3 expression, lysing GSDMD/E to mediate pyroptosis (100) and activating RIPK3 to induce MLKL phosphorylation and necroptosis (101). It has been hypothesized that cisplatin treatment in gastric cancer may increase chemotherapeutic sensitivity and inhibit tumor growth by inducing PANoptosis in cancer cells. However, this requires in vivo validation in clinical samples. Furthermore, another study indicated that the use of a PANoptosis score may aid in predicting gastric cancer prognosis and survival rates, as well as immunotherapy outcomes (11). PANoptosis may inhibit tumor growth and progression by stimulating inflammatory factor activity within tumor cells, thereby exacerbating PCD and inhibiting tumor cell immune evasion.

MALT lymphoma is a rare gastric tumor that originates as an indolent B-cell non-Hodgkin lymphoma within the marginal zone of the gastric lymphoid tissue (102). MALT is frequently induced by HP infection and chronic stimulation by autoantigens, and is primarily manifested as abnormal proliferation of small B lymphocytes within the gastric mucosa (103). NF-κB serves as a crucial mediator of immune responses and was first described in B lymphocytes. Activation of NF-κB stimulates unlimited B-cell proliferation and the transcription of antiapoptotic genes, ultimately contributing to lymphoma development (104). During chronic HP-induced inflammatory infection, released bacterial dsDNA is recognized by the cytoplasmic DNA sensor cGAS (3), triggering a DNA damage response that activates the STING-TBK1-IRF3 signaling pathway (105), consequently promoting formation of the ZBP1/CASP-8/RIPK3/ASC multiprotein complex. This further induces MLKL phosphorylation, CASP-3 cleavage and GSDME cleavage (106), thereby promoting gastric lymphoma cell death and inhibiting tumor cell proliferation. These findings demonstrate that STING suppresses MALT tumor formation by mediating PANoptosis. However, STING activation may simultaneously promote NF-κB activation and production of the proinflammatory cytokines TNF-α and IL-6 (84). On the one hand, this induces B-cell proliferation (Fig. 6), potentially driving MALT progression; however, it may also amplify the effects of PANoptosis within MALT, enhancing antitumor immune responses. Traditional anti-HP targeted therapy has a notable effect on early HP-infection type MALT lymphoma (107), but its efficacy is poor for advanced non-HP-infection type MALT lymphoma (108). However, PANoptosis-targeted therapy can induce lymphoma cell-specific death while modulating the immunosuppressive state of the tumor microenvironment. When combined with HP eradication therapy, it may improve the cure rate of early lesions and reduce the risk of recurrence. Consequently, understanding the activation of PANoptosis and investigating its balanced targets may hold key therapeutic potential for MALT.