biostudies-literatureOuyang SXFundamental Research Funds for the Central UniversitiesShanghai Shuguang ProgramShanghai "Rising Stars of Medical Talent" Youth Development Program-Youth Medical Talents-Clinical Pharmacist ProgramNational Natural Science Foundation of ChinaShanghai Science and Technology CommissionShanghai Municipal Three Year Action Plan for Strengthening the Construction of Public Health Systeme2305715https://www.ebi.ac.uk/biostudies/studies/S-EPMC11040357biostudies-literatureUnknown11(16)Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4⁺ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C⁺ monocyte infiltration, MerTk⁺ macrophages depletion, Advanced science (Weinheim, Baden-Wurttemberg, Germany)Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.PMC1104035719140904900821045308197130682073915SHWRS(2020)_087GWVI-11.2-XD0622120210560822740309184913521S119012002019CXJQ0319SG321914090470021XD1424900Liu JOuyang SXFu JTSun SJWu JWLiu YWang PZhu JHZhang ZZhang YChen YTLi DJShen FMTong JZhang JBCao QfalseGasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4⁺ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C⁺ monocyte infiltration, MerTk⁺ macrophages depletion, 2024-01-01T00:00:00Z2024 Apr2026-06-01T23:56:10.833Z2026-05-24T03:07:32.069ZS-EPMC110403573841711710.1002/advs.202305715