Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-11
·
IF 9.6
Chu Xiufeng,Zhang Ting,Bukhari Ihtisham,Hu Mei,Xu Jixuan,Xing Yamin,Liang Xinfeng,Zhang Zisen,Zheng Pengyuan
Gasdermin D (GSDMD) is a critical pyroptosis mediator, consisting of one N-terminal pore-forming domain and one C-terminal auto-inhibitory domain. The free N-terminal domain (GD-NT), which is released through caspase-1/11 cleavage, exhibits distinct features from the full-length GSDMD (GD-FL), including oligomerization, membrane translocation, and pore-formation. However, the underlying mechanisms are not well elucidated. Here, we found that GD-NT, but not GD-FL, was massively ubiquitinated in cells. The K63-linked polyubiquitination of GD-NT at Lys236/237 (human/mouse), catalyzed by TRAF1, directly prompted its membrane translocation and pore-formation during pyroptosis. Inhibition of GD-NT ubiquitination via site-directed mutations or the UBA1 inhibitor PYR-41 suppressed cell death in several pyroptosis cell models. Additionally, applying PYR-41 in septic mice efficiently suppressed the release of IL-18 and TNFα. Thus, GD-NT ubiquitination is a key regulatory mechanism controlling its membrane localization and activation, which may provide a novel target for modulating immune activity in pyroptosis-related diseases.
研究领域:
免疫学
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细胞生物学
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Shuo Zhang,Shuang Guo,Pengyu Wang,Yan Song,Leiming Yang,Qiyu Sun,Qi Huang,Youzhi Zhang
Background Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear. Methods The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits. Results Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin. Conclusion Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.
研究领域:
医学
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分子生物学
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IMMUNITY
·
2025
·
IF 26.3
Qianzhou Yu,Danlu Jiang,Tianming Zhao,Yuelin Guan,Jian Zhang,Dehang Yang,Ruya Sun,Weiwei Yu,Zhen Wang,Sheng Chen,Mobai Li,Tianyi Hu,Qiqi Deng,Xiaoyang Lu,Yidong Yang,Mengfei Chang,Liheng Du,Xue Zhang,Zhexu Chi,Di Wang
The small intestine (SI) absorbs nutrients and acts as a barrier against pathogens. Diet enables the absorptive function of the SI while maintaining immune homeostasis. But how the SI transmits nutritional signals to the immune response and adapts to dietary intake remains unclear. Here, we demonstrated that epithelial gasdermin D (GSDMD) in the SI facilitated the absorptive function of enterocytes, subsequently empowering an epithelial-immune cooperation to modulate host defense. Unlike its pyroptotic function, GSDMD determines the absorptive versus the defensive zonation of enterocytes and promotes brush border assembly. This diet-induced, GSDMD-mediated adaptation promoted lipid absorption and subsequently rewired enterocyte metabolism to support intraepithelial γδ T lymphocytes (γδ T-IELs), thereby enhancing barrier function. Impairment of this GSDMD-mediated circuit exacerbated barrier-dysfunction-associated enteritis. Our results reveal how epithelial cells and lymphocytes co-adapt to nutrient signals in the SI, thereby adjusting the equilibrium between nutrient uptake and host defense in response to environmental change.
研究领域:
免疫学
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细胞生物学
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营养学
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胃肠病学
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分子生物学
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
·
IF 3.432
Xiaomin Xia,Bin Lu,Wenjing Dong,Bingwei Yang,Yawen Wang,Qi Qin,Zixuan Liu,Erqun Song,Yang Song
Our previous study showed that tetrachlorobenzoquinone (TCBQ) mediated the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, which involves K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage. In addition, TCBQ down-regulates NLRP3 ubiquitination and promotes the activation of NLRP3 inflammasome. However, the induction of NLRP3 inflammasome by atypical pathways has not yet been characterized. Using human umbilical vein endothelial cells (HUVEC), we discovered that TCBQ activates caspase 1/4/5 and cleaves gasdermin D (GSDMD) into N-terminal and C-terminal cleavage products. In parallel, TCBQ also activates receptor interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling pathways. The N-terminal fragments of GSDMD and MLKL translocate from cytoplasm to cell membrane and form oligomers and membrane pores on the cell membrane. The formation of membrane pores not only promotes the extracellular secretion of interleukin 1 beta (IL-1β) but also affects cellular ion homeostasis, in particular promotes K+ outflow, which further activates NLRP3 inflammasome and aggravates cellular inflammation. These results indicated that GSDMD and MLKL play important roles in TCBQ-induced endothelial pro-inflammatory responses, which may point to potential therapeutic approaches for TCBQ-mediated toxicity.
研究领域:
毒理学
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免疫学
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细胞生物学
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药理学
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BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Yiling Mei,Xudong Chen,Si Shi,Wante Lin,Zhenfeng Cheng,Xiaoxi Fan,Wenqi Wu,Jibo Han,Weijian Huang,Bozhi Ye,Shanshan Dai
Background and Purpose Myocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)-mediated pyroptosis has shown promise in mitigating sepsis-induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI-Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI-Y2 offers a cardioprotective effect in the context of sepsis-induced myocardial dysfunction. Experimental Approach A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI-Y2 or macrophage membrane-encapsulated GI-Y2 nanoparticles (GI-Y2@MM-NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI-Y2 in treating septic cardiomyopathy. Key Results We observed that GI-Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI-Y2 reduced macrophage pyroptosis and attenuated macrophage-mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI-Y2 against LPS-induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI-Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI-Y2@MM-NPs to enhance the targeting capability of GI-Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo . Conclusion and Implications These findings indicate that GI-Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD-mediated pyroptosis and mitochondrial damage. Both GI-Y2 and GI-Y2@MM-NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction. Graphical
研究领域:
免疫学
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心脏病学
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药理学
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分子生物学
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ACS Nano
·
2026
·
IF 17.3
Lin Liu,Xiuxiu Wang,Xinran Song,Hui Huang,Xiaoyu Geng,Xue Wang,Wei Yan,Tianming Xu,Meiqi Chang,Yu Chen,Jishun Yang
Jellyfish envenomation poses a significant clinical challenge, with Nemopilema nomurai (N. nomurai) venom capable of inducing life-threatening hepatotoxicity through mechanisms that remain poorly understood. Here, we demonstrate that its tentacle extract (TE) simultaneously triggers a reactive oxygen species (ROS) burst, activates the canonical NLRP3/Caspase-1/Gasdermin D (GSDMD) pyroptosis pathway, and induces ZDHHC9-dependent GSDMD palmitoylation, collectively contributing to hepatic injury. To counteract this dual-pathway activation, we engineered ultrasmall iridium nanoantidotes (Ir NAs) with multienzyme mimetic activities, which effectively scavenge ROS, thereby suppressing both NLRP3 inflammasome activation and GSDMD palmitoylation while preserving mitochondrial function. These nanoantidotes significantly attenuated hepatocyte pyroptosis and histopathological damage, reduced mortality in vivo, and exhibited favorable biocompatibility with rapid clearance. Our work not only identifies GSDMD palmitoylation as a critical event in jellyfish venom-induced hepatotoxicity but also presents a translatable nanotherapeutic strategy for marine envenomation and related inflammatory disorders.
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IMMUNITY
·
2023
·
IF 32.4
Rui Miao,Cong Jiang,Winston Y. Chang,Haiwei Zhang,Jinsu An,Felicia Ho,Pengcheng Chen,Han Zhang,Caroline Junqueira,Dulguun Amgalan,Felix G. Liang,Junbing Zhang,Charles L. Evavold,Iva Hafner-Bratkovič,Zhibin Zhang,Pietro Fontana,Shiyu Xia,Markus Waldeck-Weiermair,Youdong Pan,Thomas Michel,Liron Bar-Peled,Hao Wu,Jonathan C. Kagan,Richard N. Kitsis,Peng Zhang,Xing Liu,Judy Lieberman
Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.
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Animal Models and Experimental Medicine
·
2024
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IF 3.8
Xue Wang,Chunyou Ning,Xingyi Cheng,Zhengzhong Wu,Dongbo Wu,Xuemei Ding,Cunxiang Ju,Zhihang Zhou,Lingfeng Wan,Wei Zhao,Peiliang Shi
Background The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular disintegration, which in turn liberates substantial quantities of pro-inflammatory intracellular substances, thereby accelerating the advancement of liver fibrosis. Consequently, directing therapeutic efforts towards inhibiting pyroptosis could potentially serve as an innovative approach in managing inflammation related chronic hepatic disorders. Methods GSDMD-NT ki/wt mice and Alb-cre ki/wt mice were generated using CRISPR/Cas9 technology. After crossing the two strains together, we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis. We analyzed differentially expressed genes by RNA sequencing and explored their biological functions. The efficacy of obeticholic acid (OCA) in the treatment of liver fibrosis was assessed. Results Doxycycline-treated GSDMD-NT ki/wt × Alb-cre ki/wt mice showed severe liver damage, vacuolation of hepatocytes, increased collagen fibers, and accumulation of lipid droplets. The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver. RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses, cell activation, and metabolic processes. Treatment with OCA alleviated the liver fibrosis, with reduced ALT and AST levels seen in the GSDMD-NT ki/wt × Alb-cre ki/wt mice. Conclusions We successfully constructed a novel mouse model for liver fibrosis. This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism. Our results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD-NT induced fibrosis by mediating lipid metabolism.
研究领域:
肝病学
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分子生物学
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遗传学
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Advanced Science
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2026
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IF 14.1
Dan Zhao,Lingling Zhang,Yue Wen,Lianghui Cheng,Sidan Tian,Fanling Meng,Liang Luo
Pyroptosis holds great promise for evoking robust anti‐tumor immunity, but many pyroptosis induction strategies rely on caspase‐3 (Casp‐3) activation and face challenges of the immunosuppressive nature of apoptosis and the frequent silencing of gasdermin E (GSDME), a substrate of Casp‐3, in tumors. Here, we report a strategy to rewire the pyroptotic pathway by bypassing Casp‐3 to directly activate gasdermin D (GSDMD). We identify a small‐molecule agonist, (E)‐2,3‐diiodobut‐2‐ene‐1,4‐diol (DIBDO), which undergoes deiodination to release iodide ions upon activation by the tumor‐abundant nucleophile glutathione, thereby catalytically generating singlet oxygen and molecular iodine. This cascade induces oxidative damage that downregulates key mediators of caspase‐9 and caspase‐8 pathways, thereby down‐regulating Casp‐3 activation. This mechanism selectively triggers GSDMD‐mediated pyroptosis, provoking robust immunogenic cell death and inflammatory cytokine release to reconfigure the tumor immune microenvironment. In murine tumor models, DIBDO enhances tumor infiltration of cytotoxic T cells and synergizes with checkpoint blockade therapy to suppress both primary and distal tumors. It can also serve as an in situ or exogenous vaccine to elicit potent and durable antitumor immunity. This work presents a paradigm‐shifting approach to cancer immunotherapy by decoupling pyroptosis from Casp‐3 dependence, offering a promising avenue to expand the scope of immunogenic cell death‐based treatments. This work introduces a small‐molecule agonist, DIBDO, that bypasses Casp‐3 to directly trigger GSDMD‐mediated pyroptosis in tumors. Activated by glutathione, DIBDO generates singlet oxygen and molecular iodine, blocking Casp‐3 pathways and inducing immunogenic cell death. This reconfigures the tumor microenvironment, transforms the tumor cells into in situ or exogenous vaccine, offering a novel paradigm for cancer immunotherapy.
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Drug Design Development and Therapy
·
2022
·
IF 4.319
Bozhi Ye,Xudong Chen,Shanshan Dai,Jibo Han,Xiaohe Liang,Shuang Lin,Xueli Cai,Zhouqing Huang,Weijian Huang
Background Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes.Materials and methods Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes’ ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA.Results The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins.Conclusion This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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Journal for ImmunoTherapy of Cancer
·
2026
·Vol. 14
·期 5
·e014533
·
IF 11.7
Qindan Du,Zhen Han,Yumeng Zhang,Ying Li,Ao Sun,Bin Wang,Yongquan Chen,Xiaoying Wang
Background The N-terminal domain of gasdermin D (GSDMD) is a known suppressor of prostate cancer (PCa), primarily recognized for its tumoricidal pyroptotic function. However, research on the full-length GSDMD protein and its relationship with PCa remains unexplored. Therefore, the aim of this study was to investigate the potential non-pyroptotic mechanism of action of GSDMD in preventing PCa immune evasion. Methods The study used GSDMD deletion models to assess its impact on tumor progression and immune cell profiles. Molecular techniques, including protein interaction analysis, were employed to identify the binding partner of GSDMD and the subsequent signaling pathways. Correlative analysis was performed between GSDMD expression and immune markers in human PCa samples. Results GSDMD deletion increased tumor progression and reduced survival, cytotoxic T lymphocyte (CTL) activation/infiltration and tumor cell susceptibility to T-cell death, promoting an immunosuppressive tumor microenvironment (TME). GSDMD-bound laminin subunit gamma-2 (LAMC2), thus inducing its ubiquitin-mediated degradation. Consequently, GSDMD deficiency stabilized LAMC2, driving M2 macrophage polarization and CXC motif chemokine ligand 5 (CXCL5) secretion. CXCL5 interacted with CXCR2 to activate the AKT/NF-κB axis, increasing vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and suppressing CTL activity. GSDMD expression in human PCa positively correlated with CD8 + T-cell infiltration and negatively with M2-phenotype tumor-associated macrophages. Conclusion This study reveals a novel non-pyroptotic pathway through which GSDMD inhibits PCa immune evasion by targeting LAMC2 for degradation, thereby preventing the establishment of an immunosuppressive TME. The findings suggest that activating GSDMD represents a promising therapeutic strategy to reprogram the TME from immunosuppressive (“cold”) to immunoreactive (“hot”), potentially enhancing the efficacy of immunotherapy in advanced PCa.
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PHYTOMEDICINE
·
2026
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IF 11.3
Yujuan Li,Jingyi Yang,Xiaotong Shao,Yunhe Tao,Shihui Ling,Xiaomeng Li,Qifeng Ye,Bin Guo,Hongsheng Bi
Despite advancements in treatments such as atropine, the pathological changes in high myopia still lead to vision loss, highlighting the need to identify novel therapeutic targets. Clinically, axial elongation are closely related to reduced choroidal blood flow. This study revealed that the pyroptosis-associated protein Gasdermin D (GSDMD) may play a key role in high myopia. Experiments showed that chemical inhibition of GSDMD significantly reduced axial elongation and choroidal blood flow reduction. Furthermore, by screening pharmacologically active traditional Chinese medicine compounds, we identified that Artemisia argyi (Aiye) and its active ingredient apigenin act as effective GSDMD inhibitors, capable of replicating the protective effects observed with chemical inhibition. In all, this study suggests that GSDMD is a potential target mediating axial elongation and choroidal blood flow changes in high myopia, and apigenin is a potential therapeutic strategy for intervening in high myopia.
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