Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19.

The COVID-19 pandemic was caused by the recently emerged ß-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

Caspases in Cell Death, Inflammation, and Pyroptosis.

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D-induced pyroptosis.

NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes.

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.

Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense.

Caspases regulate cell death, immune responses, and homeostasis. Caspase-6 is categorized as an executioner caspase but shows key differences from the other executioners. Overall, little is known about the functions of caspase-6 in biological processes apart from apoptosis. Here, we show that caspase-6 mediates innate immunity and inflammasome activation. Furthermore, we demonstrate that caspase-6 promotes the activation of programmed cell death pathways including pyroptosis, apoptosis, and necroptosis (PANoptosis) and plays an essential role in host defense against influenza A virus (IAV) infection. In addition, caspase-6 promoted the differentiation of alternatively activated macrophages (AAMs). Caspase-6 facilitated the RIP homotypic interaction motif (RHIM)-dependent binding of RIPK3 to ZBP1 via its interaction with RIPK3. Altogether, our findings reveal a vital role for caspase-6 in facilitating ZBP1-mediated inflammasome activation, cell death, and host defense during IAV infection, opening additional avenues for treatment of infectious and autoinflammatory diseases and cancer.

The NLR family of innate immune and cell death sensors.

Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.

PANoptosis: Mechanisms, biology, and role in disease.

Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer. Given the impact of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and PANoptosis activation, and outlines the multifaceted roles of PANoptosis in diseases together with a potential for therapeutic targeting. We also discuss important concepts and pressing issues for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is crucial for identifying novel therapeutic targets and strategies.

Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.

Inflammasomes are multi-protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), driving the secretion of the pro-inflammatory cytokines IL-1ß and IL-18, and pyroptosis. The best-characterized inflammasome complexes are the NLRP3, NAIP-NLRC4, NLRP1, AIM2, and Pyrin canonical caspase-1-containing inflammasomes, and the caspase-11 non-canonical inflammasome. Newer inflammasome sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, and MxA. These inflammasome sensors can sense PAMPs from bacteria, viruses and protozoa, or DAMPs in the form of mitochondrial damage, ROS, stress and heme. The mechanisms of action, physiological relevance, consequences in human diseases, and avenues for therapeutic intervention for these novel inflammasomes are beginning to be realized. Here, we discuss these emerging inflammasome complexes and their putative activation mechanisms, molecular and signaling pathways, and physiological roles in health and disease.

PANoptosis, an indicator of COVID-19 severity and outcomes.

Coronavirus disease 2019 (COVID-19) has been wreaking havoc for 3 years. PANoptosis, a distinct and physiologically relevant inflammatory programmed cell death, perpetuates cytokine storm and multi-organ injuries in COVID-19. Although PANoptosis performs indispensable roles in host defense, further investigation is needed to elucidate the exact processes through which PANoptosis modulates immunological responses and prognosis in COVID-19. This study conducted a bioinformatics analysis of online single-cell RNA sequence (scRNA-seq) and bulk RNA-seq datasets to explore the potential of PANoptosis as an indicator of COVID-19 severity. The degree of PANoptosis in bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) indicated the severity of COVID-19. Single-cell transcriptomics identified pro-inflammatory monocytes as one of the primary sites of PANoptosis in COVID-19. The study subsequently demonstrated the immune and metabolic characteristics of this group of pro-inflammatory monocytes. In addition, the analysis illustrated that dexamethasone was likely to alleviate inflammation in COVID-19 by mitigating PANoptosis. Finally, the study showed that the PANoptosis-related genes could predict the intensive care unit admission (ICU) and outcomes of COVID-19 patients who are hospitalized.

ADAR1 and ZBP1 in innate immunity, cell death, and disease.

ADAR1 and ZBP1 are the only two mammalian proteins that contain Zα domains, which are thought to bind to nucleic acids in the Z-conformation. These two molecules are crucial in regulating diverse biological processes. While ADAR1-mediated RNA editing supports host survival and development, ZBP1-mediated immune responses provide host defense against infection and disease. Recent studies have expanded our understanding of the functions of ADAR1 and ZBP1 beyond their classical roles and established their fundamental regulation of innate immune responses, including NLRP3 inflammasome activation, inflammation, and cell death. Their roles in these processes have physiological impacts across development, infectious and inflammatory diseases, and cancer. In this review, we discuss the functions of ADAR1 and ZBP1 in regulating innate immune responses in development and disease.

Interplay of ferroptosis, cuproptosis, and PANoptosis in cancer treatment-induced cardiotoxicity: Mechanisms and therapeutic implications.

With the prolonged survival of individuals with cancer, the emergence of cardiovascular diseases (CVD) induced by cancer treatment has become a significant concern, ranking as the second leading cause of death among cancer survivors. This review explores three distinct types of programmed cell death (PCD): ferroptosis, cuproptosis, and PANoptosis, focusing on their roles in chemotherapy-induced cardiotoxicity. While ferroptosis and cuproptosis are triggered by excess iron and copper (Cu), PANoptosis is an inflammatory PCD with features of pyroptosis, apoptosis, and necroptosis. Recent studies reveal intricate connections among these PCD types, emphasizing the interplay between cuproptosis and ferroptosis. Notably, the role of intracellular Cu in promoting ferroptosis through GPX4 is highlighted. Additionally, ROS-induced PANoptosis is influenced by ferroptosis and cuproptosis, suggesting a complex interrelationship. This review provides insights into the molecular mechanisms of these PCD modalities and their distinct contributions to chemotherapy-induced cardiotoxicity. Furthermore, we discuss the potential application of cardioprotective drugs in managing these PCD types. This comprehensive analysis aims to advance the understanding, diagnosis, and therapeutic strategies for cardiotoxicity associated with cancer treatment.

Classical apoptotic stimulus, staurosporine, induces lytic inflammatory cell death, PANoptosis.

Innate immunity is the body's first line of defense against disease, and regulated cell death is a central component of this response that balances pathogen clearance and inflammation. Cell death pathways are generally categorized as non-lytic and lytic. While non-lytic apoptosis has been extensively studied in health and disease, lytic cell death pathways are also increasingly implicated in infectious and inflammatory diseases and cancers. Staurosporine (STS) is a well-known inducer of non-lytic apoptosis. However, in this study, we observed that STS also induces lytic cell death at later timepoints. Using biochemical assessments with genetic knockouts, pharmacological inhibitors, and gene silencing, we identified that STS triggered PANoptosis via the caspase-8/RIPK3 axis, which was mediated by RIPK1. PANoptosis is a lytic, innate immune cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. Deletion of caspase-8 and RIPK3, core components of the PANoptosome complex, protected against STS-induced lytic cell death. Overall, our study identifies STS as a time-dependent inducer of lytic cell death, PANoptosis. These findings emphasize the importance of understanding trigger- and time-specific activation of distinct cell death pathways to advance our understanding of the molecular mechanisms of innate immunity and cell death for clinical translation.

PANoptosis is a prominent cell death feature in thoracic aortic aneurysm or dissection.

Thoracic aortic aneurysm and dissection (TAAD) is a devastating macrovascular disease, and its pathogenic mechanisms have not been well clarified. This study aimed to investigate the role of PANoptosis, which is newly defined programmed cell death (PCD) and characterized by pyroptosis, apoptosis, and necroptosis, in the pathogenesis of TAAD. We found that the expression of initiator factor Z-DNA binding protein 1 (ZBP1) and PANoptosis-related genes were upregulated in the ß-aminopropionitrile (BAPN) + Angiotensin II (Ang II)-induced TAAD mice. Ang II stimuli enhanced the expression of ZBP1, promoted the generation of bioactive GSDMD (Gasdermin D) fragments, the cleavage of Caspase 3, and increased the phosphorylation of mixed lineage kinase domain-like pseudokinase (MLKL) in human aortic vascular smooth muscle cells (HASMCs), indicating the activation of hallmarks for PANoptosis. Moreover, ZBP1-mediated PANoptosis occurs in the aortic tissues of TAAD patients. These results highlight the significant role of PANoptosis in TAAD pathogenesis, suggesting ZBP1 and other PANoptosis-related genes as potential therapeutic targets for this condition.

Sulconazole Induces PANoptosis by Triggering Oxidative Stress and Inhibiting Glycolysis to Increase Radiosensitivity in Esophageal Cancer.

Esophageal cancer is the seventh most common cancer in the world. Although traditional treatment methods such as radiotherapy and chemotherapy have good effects, their side effects and drug resistance remain problematic. The repositioning of drug function provides new ideas for the research and development of anticancer drugs. We previously showed that the Food and Drug Administration-approved drug sulconazole can effectively inhibit the growth of esophageal cancer cells, but its molecular mechanism is not clear. Here, our study demonstrated that sulconazole had a broad spectrum of anticancer effects. It can not only inhibit the proliferation but also inhibit the migration of esophageal cancer cells. Both transcriptomic sequencing and proteomic sequencing showed that sulconazole could promote various types of programmed cell death and inhibit glycolysis and its related pathways. Experimentally, we found that sulconazole induced apoptosis, pyroptosis, necroptosis, and ferroptosis. Mechanistically, sulconazole triggered mitochondrial oxidative stress and inhibited glycolysis. Finally, we showed that low-dose sulconazole can increase radiosensitivity of esophageal cancer cells. Taken together, these new findings provide strong laboratory evidence for the clinical application of sulconazole in esophageal cancer.

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis.

BACKGROUND: The innate immune system serves as the first line of host defense. Transforming growth factor-ß-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease. RESULTS: In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation. CONCLUSIONS: Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.

PANoptosis in vascular smooth muscle cells regulated by TNF-α/IL-1ß can be a new target for alleviating the progression of abdominal aortic aneurysm.

PANoptosis is an inflammatory programmed cell death (PCD) regulated by multifaceted PANoptosome complexes with major features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. The aim of this study was to investigate the role of PANoptosis on the occurrence and development of abdominal aortic aneurysm (AAA). Clinical samples of patients with AAA, angiotensin II (ANG II)-induced AAA mouse model, and ANG II-induced vascular smooth muscle cells (VSMCs) in vitro model were used for investigation on PANoptosis features. The expressions of ZBP1, AIM2, and other markers related to pyroptosis, apoptosis, and necroptosis elevated obviously in aortic wall tissues of patients with AAA, mice with AAA, and ANG II-treated VSMCs. ANG II treatment increased inflammatory cytokines levels in VSMCs. The stimulation of tumor necrosis factor-α (TNF-α) or interleukin-1ß (IL-1ß) alone promoted VSMCs death, and the effect of TNF-α combined with IL-1ß is more obvious. The expressions of ZBP1, AIM2, and related markers of pyroptosis, apoptosis, and necroptosis were increased by TNF-α and IL-1ß combined treatment. Inhibition of TNF-α and/or IL-1ß in mice with AAA improved the AAA pathology, reduced the loss of VSMCs, decreased the expression of ZBP1 and AIM2, and markers associated with pyroptosis, apoptosis, and necroptosis. PANoptosis features were observed in aortic wall tissues of patients with AAA, mice with AAA, and ANG II-treated VSMCs. The inhibition of TNF-α and IL-1ß can alleviate PANoptosis in mice with AAA, which provides a new strategy for the prevention and treatment of AAA.NEW & NOTEWORTHY Early detection, diagnosis, and treatment are very important to improve the quality of life and prognosis of patients with abdominal aortic aneurysm (AAA). Based on the findings of apoptosis, necroptosis, and pyroptosis (PANoptosis) in AAA clinical samples, this study further explored the molecular mechanism in vivo and in vitro. Specifically, inhibition of tumor necrosis factor-α and interleukin-1ß can reduce PANoptosis in vascular smooth muscle cell and thus alleviate the process of AAA.

Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis).

The innate immune system provides the first line of defense against pathogens and cellular insults and is activated by pattern recognition receptors sensing pathogen- or damage-associated molecular patterns. This activation can result in inflammation via cytokine release as well as the induction of lytic regulated cell death (RCD). Innate immune signaling can also induce the expression of interferon regulatory factor 1 (IRF1), an important molecule in regulating downstream inflammation and cell death. While IRF1 has been shown to modulate some RCD pathways, a comprehensive evaluation of its role in inflammatory cell death pathways is lacking. Here, we examined the role of IRF1 in cell death during inflammasome and PANoptosome activation using live cell imaging, Western blotting, and ELISA in primary murine macrophages. IRF1 contributed to the induction of ZBP1- (Z-DNA binding protein 1), AIM2- (absent in melanoma-2), RIPK1- (receptor interacting protein kinase 1), and NLRP12 (NOD-like receptor family, pyrin domain-containing 12)-PANoptosome activation and PANoptosis. Furthermore, IRF1 regulated the cell death under conditions where inflammasomes, along with caspase-8 and RIPK3, act as integral components of PANoptosomes to drive PANoptosis. However, it was dispensable for other inflammasomes that form independent of the PANoptosome to drive pyroptosis. Overall, these findings define IRF1 as an upstream regulator of PANoptosis and suggest that modulating the activation of molecules in the IRF1 pathway could be used as a strategy to treat inflammatory and infectious diseases associated with aberrant inflammatory cell death.

Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD.

Chronic inflammatory and immune responses play key roles in the development and progression of chronic obstructive pulmonary disease (COPD). PANoptosis, as a unique inflammatory cell death modality, is involved in the pathogenesis of many inflammatory diseases. We aim to identify critical PANoptosis-related biomarkers and explore their potential effects on respiratory tract diseases and immune infiltration landscapes in COPD. Total microarray data consisting of peripheral blood and lung tissue datasets associated with COPD were obtained from the GEO database. PANoptosis-associated genes in COPD were identified by intersecting differentially expressed genes (DEGs) with genes involved in pyroptosis, apoptosis, and necroptosis after normalizing and removing the batch effect. Furthermore, GO, KEGG, PPI network, WGCNA, LASSO-COX, and ROC curves analysis were conducted to screen and verify hub genes, and the correlation between PYCARD and infiltrated immune cells was analyzed. The effect of PYCARD on respiratory tract diseases and the potential small-molecule agents for the treatment of COPD were identified. PYCARD expression was verified in the lung tissue of CS/LPS-induced COPD mice. PYCARD was a critical PANoptosis-related gene in all COPD patients. PYCARD was positively related to NOD-like receptor signaling pathway and promoted immune cell infiltration. Moreover, PYCARD was significantly activated in COPD mice mainly by targeting PANoptosis. PANoptosis-related gene PYCARD is a potential biomarker for COPD diagnosis and treatment.

Global trends in PANoptosis research: bibliometrics and knowledge graph analysis.

PANoptosis has recently been discovered as a new type of cell death. PANoptosis mainly refers to the significant interaction among the three programmed cell death pathways of apoptosis, necroptosis, and pyroptosis. Despite this, only a few studies have examined the systematic literature in this area. By analyzing the bibliometric data for PANoptosis, we can visualize the current hotspots and predicted trends in research. This study analyzed bibliometric indicators using the Histcite Pro 2.0 tool, which searches the Web of Science for PANoptosis literature published between 2016 and 2022. A bibliometric analysis was performed using Histcite Pro 2.0, while research trends and hotspots were visualized using VOSviewer, CiteSpace and BioBERT. The output of related literature was low in the four years from the first presentation of PANoptosis in 2016 to 2020. The volume of relevant literature grew exponentially between 2020 and 2022. The United States and China play a leading role in this field. Although China started late, its research in this field is developing rapidly. As research progressed, more focus was placed on the relationship between PANoptosis and pyroptosis, as well as apoptosis and necrosis. Now is a rapid development stage of PANoptosis research. Most of the research focuses on the cellular level, and the focus is more on the treatment of tumor-related diseases. The current focus of this area is PANoptosis mechanisms in cancer and inflammation. It can be seen from the burst analysis of keywords that caspase1 and host defense have consistently been research hotspots in the field of PANoptosis, while the frequency of NLRC4, causes of autoinflammation, recognition, NLRP3, and Gasdermin D has gradually increased, all of which have become research hotspots in recent years. Finally, we used the BioBERT biomedical language model to mine the most documented genes and diseases in the PANoptosis field articles, pointing out the direction for subsequent research steps. According to a bibliometric analysis, researchers have shown an increased interest in PANoptosis over the past few years. Researchers initially focused on the molecular mechanism of PANoptosis and pyroptosis, apoptosis, and necroptosis. The role of PANoptosis in diseases and conditions such as inflammation and tumors is one of the current research hotspots in this area. The focus is more on treating inflammation-related diseases, which will become the key development direction of future research.

PANoptosis subtypes predict prognosis and immune efficacy in gastric cancer.

PANoptosis is a form of inflammatory programmed cell death that is regulated by the PANoptosome. This PANoptosis possesses key characteristics of pyroptosis, apoptosis, and necroptosis, yet cannot be fully explained by any of these cell death modes. The unique nature of this cell death mechanism has garnered significant interest. However, the specific role of PANoptosis-associated features in gastric cancer (GC) is still uncertain. Patients were categorized into different PAN subtypes based on the expression of genes related to the PANoptosome. We conducted a systematic analysis to investigate the variations in prognosis and tumor microenvironment (TME) among these subtypes. Furthermore, we developed a risk score, called PANoptosis-related risk score (PANS), which is constructed from genes associated with the PANoptosis. We comprehensively analyzed the correlation between PANS and GC prognosis, TME, immunotherapy efficacy and chemotherapeutic drug sensitivity. Additionally, we performed in vitro experiments to validate the impact of Keratin 7 (KRT7) on GC. We identified two PAN subtypes (PANcluster A and B). PANoptosome genes were highly expressed in PANcluster A. PANcluster A has the characteristics of favorable prognosis, abundant infiltration of anti-tumor lymphocytes, and sensitivity to immunotherapy, thus it was categorized as an immune-inflammatory type. Meanwhile, our constructed PANS can effectively predict the prognosis and immune efficacy of GC. Patients with low PANS have a good prognosis, and have the characteristics of high tumor mutation load (TMB), high microsatellite instability (MSI), low tumor purity and sensitivity to immunotherapy. In addition, PANS can also identify suitable populations for different chemotherapy drugs. Finally, we confirmed that KRT7 is highly expressed in GC. Knocking down the expression of KRT7 significantly weakens the proliferation and migration abilities of GC cells. The models based on PANoptosis signature help to identify the TME features of GC and can effectively predict the prognosis and immune efficacy of GC. Furthermore, the experimental verification results of KRT7 provide theoretical support for anti-tumor treatment.