PDF(Pubmed)
Abstract：
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, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.
摘要：
药物性肝损伤（DILI）是一个重要的全球健康问题，具有很高的死亡率和发病率风险。DILI的一个常见原因是对乙酰氨基酚(APAP)过量。GSDME是诱导非规范焦亡的效应蛋白。在这项研究中,GSDME的激活，但不是GSDMD，据报道，小鼠和患者的肝脏组织中存在APAP-DILI。GSDME的淘汰,而不是GSDMD，在小鼠中保护它们免受APAP-DILI的侵害。肝细胞特异性拯救GSDME的小鼠再现了APAP诱导的肝损伤。此外，在APAP诱导的DILI中观察到的免疫细胞库的改变，例如用单核细胞衍生的KC替换TIM4+常驻Kupffer细胞（KC），Ly6C+单核细胞浸润，MerTk+巨噬细胞消耗，中性粒细胞增加，在肝细胞特异性抢救GSDME的小鼠中再次出现。机械上,APAP暴露导致干扰素刺激基因15（ISG15）的大量损失，导致氨基甲酰磷酸合成酶-1（CPS1）的去ISG化，通过K48连接的泛素化促进其降解，导致氨清除功能障碍。GSDME删除阻止了这些影响。延迟施用富马酸二甲酯抑制GSDME裂解并减轻氨积累，减轻肝损伤。这一发现证明了GSDME在APAP-DILI中通过促进焦凋亡和CPS1去ISG化的先前未表征的作用，表明抑制GSDME可能是APAP-DILI的有希望的治疗选择。
