Immune checkpoint blockade (ICB) remains ineffective in most colorectal cancers (CRC) due to intrinsic immune resistance. We identify guanylate-binding protein 2 (GBP2) as a key enhancer of ICB response through modulation of the gasdermin D (GSDMD)-Yes-associated protein (YAP) axis. Analyses of CRC cohorts, patient samples, organoids, and mouse models revealed that GBP2 directly binds GSDMD, inhibiting its cleavage-dependent activation and preventing YAP nuclear translocation. Activated GSDMD facilitates YAP nuclear accumulation, which represses CXCL9/10/11 transcription and limits CD8⁺ T-cell infiltration. Mechanistically, GBP2 disrupts this process by restraining non-pyroptotic GSDMD activity and maintaining YAP in its inactive cytoplasmic state. Genetic or pharmacologic inhibition of GSDMD restored YAP inactivation and sensitized tumors to anti-PD-L1 therapy. These findings define a GBP2-GSDMD-YAP signaling axis that inhibits immune evasion and represents a therapeutic target to overcome ICB resistance in CRC.

Liver ischemia-reperfusion injury (IRI) is a sterile inflammatory process that contributes significantly to graft rejection following liver transplantation. Although SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is known to preserve genomic stability and restrain inflammation under oxidative stress, its immunoregulatory function in myeloid cells during liver IRI has not been elucidated. This study aimed to investigate the role and mechanism of SETDB1 in regulating macrophage-driven inflammatory responses in liver IRI. Myeloid-specific SETDB1 knockout (SETDB1 cKO) mice exhibited exacerbated liver injury, increased infiltration of pro-inflammatory macrophages and neutrophils, and amplified inflammatory responses compared with SETDB1fl/fl controls. Depletion of macrophages alleviated liver damage, reduced neutrophil infiltration and hepatocyte apoptosis, and eliminated the excessive injury observed in SETDB1 cKO mice. Mechanistically, SETDB1 suppressed the expression of purinergic receptor P2X7 (P2RX7). Pharmacological inhibition of P2RX7 with oxidized adenosine triphosphate significantly attenuated liver injury and macrophage infiltration in SETDB1 cKO mice. In vitro assays confirmed that SETDB1 inhibited the P2RX7/Caspase-1/Gasdermin D (GSDMD) pathway in macrophages, thereby limiting pyroptosis and inflammation. This study identifies SETDB1 as a previously unrecognized regulator of macrophage pyroptosis during liver IRI. By linking epigenetic regulation to suppression of the P2RX7/Caspase-1/GSDMD pathway, our findings provide novel mechanistic insight into how SETDB1 protects against sterile liver inflammation. SETDB1 plays a pivotal role in protecting the liver from IRI by restraining macrophage-mediated pyroptosis and inflammation. These findings suggest that targeting the SETDB1/P2RX7/Caspase-1/GSDMD axis may represent a promising therapeutic strategy for mitigating liver IRI and improving transplant outcomes. Antioxid. Redox Signal. 45, 133-148.

Intranasal administration of geniposide-baicalin treats ischemic stroke reperfusion conjugated with pneumonia by inhibiting HMGB1-mediated pyroptosis via NLRP3/Caspase-1/GSDMD pathway.

Aluminium ammonium sulphate (AAS) is a food additive used in some countries, but its effects on intestinal epithelial cells (IECs) remain poorly understood. We investigated whether AAS promotes IEC death and eosinophilic infiltration under dysbiotic conditions and whether heparin suppresses these effects. Mice pretreated with antibiotics or control water were orally administered AAS. IEC death was assessed by RNA sequencing, western blotting, and flow cytometry. Microbiota composition was analysed by 16S rRNA sequencing, and eosinophilic infiltration was evaluated by histology and flow cytometry. Immortalised murine IECs were stimulated with AAS in the presence or absence of bacterial components, and the effects of heparin were examined in vitro and in vivo. Antibiotic-induced dysbiosis altered IEC metabolic programmes and reduced polysaccharide-degrading bacteria. Under these conditions, AAS further reduced Actinobacteria, including Bifidobacterium, increased mitochondrial reactive oxygen species (mtROS), and promoted cleavage of caspase-1, caspase-6, caspase-8, caspase-11, interleukin-33, gasdermin D (GSDMD), and gasdermin E (GSDME) in IECs. These changes were associated with epithelial pyroptosis and eosinophilic infiltration in the small intestine. AAS induced similar cleavage events in IECs primed with lipopolysaccharide and lipoteichoic acid in vitro. Antioxidant studies showed that caspase-1/11-GSDMD activation was ROS-dependent, whereas caspase-6/8-GSDME activation involved ROS-independent mechanisms. Heparin suppressed these cleavage events, reduced IEC death both in vitro and in vivo, and attenuated eosinophilic inflammation. These findings identify a previously unrecognised pro-inflammatory effect of AAS in the dysbiotic gut and suggest low-dose heparin as a potential protective strategy for intestinal epithelial homoeostasis.

Lnc-USP28-6/ZBTB16 axis orchestrates NLRP3 inflammasome activation and α-synuclein SUMOylation to drive Parkinson's disease pathogenesis.

HPA deficiency alleviates tissue factor expression in sepsis-induced coagulopathy by regulating HS/NLRP3 inflammasome pathway.

Cell death regulation: A novel way of natural products to treat myocardial hypertrophy.

Diabetic nephropathy (DN) is a progressive microvascular complication of diabetes and a leading cause of end-stage renal disease, with limited disease-modifying therapeutic options. DN is characterized by progressive renal dysfunction, oxidative stress, inflammation, fibrosis, and activation of inflammasome-related pathways. Silymarin, a natural compound with antioxidant and anti-inflammatory properties, has demonstrated renoprotective potential; however, its association with miRNA-223/NLRP3/caspase-1/GSDMD signaling in DN remains incompletely defined. Therefore, the present study investigated the potential renoprotective effects of silymarin in a high-fat diet/streptozotocin (HFD/STZ)-induced rat model of DN, with particular focus on miRNA-223 expression and inflammasome-associated pyroptotic signaling. Diabetic rats received oral silymarin (100mg/kg/day) either for 12 weeks as an early intervention or 4 weeks as a delayed treatment. Renal function indices, blood glucose, HbA1c, serum insulin, HOMA-IR, LDH, lipid profile, body weight, kidney weight/body weight index, oxidative stress markers, and histopathological changes were evaluated. Renal expression of miRNA-223, NOD-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, gasdermin D (GSDMD), nuclear factor-kappa B (NF-κB) (p65), hypoxia-inducible factor-1 alpha (HIF-1α), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and fibronectin was assessed using RT-qPCR, ELISA, and immunohistochemistry. Silymarin significantly improved renal function, glycemic control, insulin resistance, lipid profile, oxidative stress, inflammatory mediators, HIF-1α expression, LDH activity, histopathological injury, and fibrosis relative to untreated DN rats. Moreover, silymarin was associated with increased renal miRNA-223 expression and reduced expression of NLRP3, caspase-1, and GSDMD. These effects were more pronounced in the early intervention group compared with delayed treatment. In conclusion, silymarin attenuated experimental DN via modulation of the miRNA-223/NLRP3/caspase-1/GSDMD axis and suppression of pyroptosis-associated signaling, alongside improvement of oxidative stress, inflammation, hypoxia, fibrosis, and metabolic disturbances. Further mechanistic studies are warranted to clarify the causal relationship between miRNA-223 modulation and the observed renoprotective effects of silymarin.

The efficacy of chemotherapeutic drugs is inherently dose-dependent, and their clinical application is often limited by systemic toxicity and poor tumor selectivity. Manganese dioxide (MnO2) nanomaterials have attracted considerable interest in nanomedicine due to their favorable biocompatibility, efficient cellular uptake, and capacity to remodel the tumor microenvironment (TME). Docetaxel (DTX) remains a first-line treatment for advanced prostate cancer; however, its considerable side effects restrict therapeutic outcomes. To enhance the efficacy of DTX while reducing its toxicity, we encapsulated DTX into hollow MnO2 nanoparticles pre-loaded with the photosensitizer IR825, constructing a multifunctional nanoplatform designated H-MnO2@IR825/DTX. This nanoplatform leverages the catalase-like activity of H-MnO2 to catalyze the decomposition of tumor-overexpressed H2O2 into O2, thereby alleviating hypoxia and providing an endogenous oxygen source for photodynamic therapy (PDT). Under near‑infrared (NIR) irradiation, H-MnO2@IR825/DTX generates both localized hyperthermia for photothermal therapy (PTT) and a burst of reactive oxygen species (ROS), which synergizes with the controlled release of DTX to achieve multimodal antitumor treatment. Mechanistically, the ROS burst not only activates the mitochondrial apoptosis pathway but also triggers pyroptosis via the NLRP3/Caspase-1/Gasdermin D (GSDMD) signaling axis, as validated by both in vitro and in vivo experiments. Meanwhile, the decomposition of MnO2 depletes glutathione (GSH) and generates Mn2+ for chemodynamic therapy (CDT), further amplifying oxidative stress. Collectively, H-MnO2@IR825/DTX integrates TME remodeling with PTT, PDT, CDT, and chemotherapy, eliciting potent synergistic antitumor effects against prostate cancer through ROS-dependent apoptosis and pyroptosis, while exhibiting low toxicity to normal cells. This rationally designed nanoplatform represents a promising strategy for effective and safe prostate cancer therapy.

Circulating ATP from hepatic ischemia-reperfusion drives remote cardiac injury via macrophage inflammasome activation.

Transient receptor potential vanilloid 4 exacerbates sepsis-induced acute lung injury by promoting endothelial pyroptosis via the Ca2+/Nrf2/GSDMD signaling pathway.

BackgroundDespite advances in the treatment of Acute Myeloid Leukemia (AML), the predictive 5-year overall survival rate is still poor not exceeding 20%. Most patients develop relapse partly due to resistance mechanisms to classical cell death programs. Currently, cytogenetic markers play a crucial role in the early diagnosis, prognostic classification, and therapy selection for AML. Yet, there is a pressing need for the discovery of novel AML biomarkers for a better understanding of the disease’s molecular mechanisms, diagnosis, prognosis assessment, and personalized therapeutic response. The role of cell death-related genes in driving AML progression and spread remains inadequately explored. Among these, ferroptosis and pyroptosis are emerging as critical mechanisms of programmed cell death that are often dysregulated in cancer.MethodsWe recruited 100 newly diagnosed AML patients and 40 healthy matched individuals. Using reverse transcription-quantitative PCR analysis, we assessed the expression levels of NFS1 and Gasdermin D (GSDMD).ResultsOur findings revealed significant NFS1 upregulation (P < 0.0001) and GSDMD downregulation (P < 0.0001) in AML patients compared to healthy controls. Following treatment, we observed a significant downregulation of NFS1 expression (P < 0.001) and upregulation of GSDMD (P < 0.001). Furthermore, higher pretreatment levels of NFS1 and lower pretreatment levels of GSDMD correlated with poor prognosis (P < 0.001) and decreased one-year survival (P < 0.001).ConclusionOur study suggests that NFS1 and GSDMD may serve as early diagnostic and prognostic markers in AML, offering potential targets for improved therapeutic strategies.

Cytidine/Uridine monophosphate kinase 2 promotes aflatoxin B1-induced hepatic pyroptosis and inflammation.

Trimethylamine N-oxide drives cardiac aging by activating NLRP3-mediated pyroptosis.

Gasdermins are a family of pore-forming proteins that regulate the release of pro-inflammatory cytokine, interleukin-1β (IL-1β) from infected or PAMP-stimulated cells. During infection or injury, IL-1β is released by both human and mouse macrophages. IL-1β release from mouse macrophages is associated with cell death, often termed “pyroptosis”. Mouse macrophages undergoing pyroptosis assemble an exit channel termed gasdermin D (GSDMD). Both the processing of IL-1β and the formation of the exit channel are caspase-1 dependent. Here, in bacterial endotoxin, lipopolysaccharide (LPS), treated mouse bone marrow-derived macrophages (BMDMs), we studied the pharmacologic inhibition of the intracellular nucleotide-binding domain, leucine-rich-containing family, pyrin domain– containing-3 (NLRP3) inflammasome by OLT1177. BMDMs stimulated with LPS plus the potassium efflux inducer nigericin triggered the formation of the NLRP3 inflammasome. Treatment of these BMDMs with OLT1177 suppressed cell death by 42% and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain)-speck formation by approximately 60%. In addition, OLT1177 dose-dependently inhibited IL-1β, CCL3, and myeloperoxidase (MPO) secretion and the pore-forming (GSDMD) from LPS-primed BMDMs, suggesting the existence of a vicious cycle controlled by IL-1β release. Overall, our study demonstrates that OLT1177 prevents IL-1β release from BMDMs by inhibiting caspase-1 and the conversion of (GSDMD) into its active N-terminal fragment (GSDMD-N). This study thus supports the concept that orally administered OLT1177 can be used to prevent local as well as systemic inflammation in humans.

The neuroprotective effect of eugenol in aluminum chloride-induced Alzheimer's rats: Insights into the role of TLR4/MyD88/NF-kB and NLRP3 inflammasome/gasdermin D signaling pathways.

Heart failure with preserved ejection fraction (HFpEF) is a common cardiovascular disorder characterized by a left ventricular ejection fraction of ≥45%, which is typically accompanied by diastolic dysfunction and symptoms of heart failure. Although dapagliflozin treatment may relieve symptoms in patients with HFpEF, the precise biological mechanisms underlying its therapeutic effects remain incompletely understood. Pyroptosis can induce inflammatory amplification and contribute to the development of cardiovascular disease. Nevertheless, the mechanism of dapagliflozin and pyroptosis in the pathogenesis and treatment of HfpEF remains largely unknown. The present study aimed to investigate the mechanism through which dapagliflozin regulates pyroptosis in HFpEF. First, a mouse model of HFpEF was established and dapagliflozin was administered to assess the phenotypes of HFpEF in mice and the level of pyroptosis in their myocardial tissues. Then, an HFpEF model of mouse cardiomyocytes was constructed, after which absent in melanoma 2 (AIM2) was knocked down and Caspase-1 was overexpressed to determine the AIM2/Caspase-1 signaling pathway in regulating pyroptosis under HFpEF conditions. Subsequently, cardiomyocytes were treated with dapagliflozin and AIM2 was overexpressed to investigate the mechanism by which dapagliflozin and AIM2 affect pyroptosis in HFpEF model cells. At the animal level, mice were treated with dapagliflozin and subjected to AIM2 overexpression to further explore the underlying mechanisms involved. Dapagliflozin alleviated the symptoms of HFpEF in mice and decreased the level of pyroptosis in the myocardial tissue of HFpEF mice. Compared with the sham group, AIM2 protein levels in the myocardial tissue of HFpEF mice were elevated and dapagliflozin treatment decreased AIM2 protein levels. Changes in pyroptosis in the myocardial tissue of HFpEF mice were accompanied by fluctuations in AIM2 protein levels. At the cellular level, AIM2 downregulation alleviated pyroptosis in mouse cardiomyocytes. Additionally, the data revealed a potential interaction between dapagliflozin and AIM2. Moreover, AIM2 regulated pyroptosis in mouse cardiomyocytes via the Caspase-1/Gasdermin D (GSDMD) axis. Lastly, it was demonstrated in vitro and in vivo that dapagliflozin may alleviate HFpEF symptoms in mice through mechanisms involving regulation of the AIM2/Caspase-1/GSDMD axis and attenuation of myocardial pyroptosis. In conclusion, dapagliflozin may alleviate HFpEF through mechanisms involving the AIM2/Caspase-1/GSDMD axis to attenuate pyroptosis, suggesting a potential therapeutic approach for the treatment of HFpEF.

Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16 weeks to establish a COPD model. In vitro, alveolar macrophages (AMs) (MH-S) and alveolar epithelial cells (MLE-12) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol-12-myristate-13-acetate (PMA)-stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis-related proteins were analyzed. Co-immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS-exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE-induced MH-S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS-induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. © 2026 The Pathological Society of Great Britain and Ireland.

Neutrophil aconitate decarboxylase 1/itaconate axis suppresses extracellular traps via alkylating GSDMD and alleviates murine liver injury.

Post-translational modifications of gasdermin D: implications for pyroptosis and autoimmune diseases.