Gasdermin E偶联病毒性焦亡与致死性肝脏脂质积累

Gasdermin E偶联病毒性焦亡与致死性肝脏脂质积累

作者： 小柯机器人 发布时间：2026/8/3 16:25:06

本期文章：《细胞》：Online/在线发表

军事科学院军事医学研究院微生物流行病研究所刘玮教授、黎浩教授团队取得一项新突破。他们开发出Gasdermin E偶联病毒性焦亡与致死性肝脏脂质积累。相关论文于2026年7月29日发表于国际顶尖学术期刊《细胞》杂志上。

小组发现，WELV感染会导致患者出现致命性肝功能障碍，其特征是肝酶升高、甘油三酯积累和高炎症。WELV通过线粒体和Fas介导的凋亡途径诱导肝细胞气真皮蛋白E （GSDME）依赖性热凋亡。病毒RNA激活RIG-I/ CASP3介导的GSDME切割，而病毒核蛋白经历CASP3依赖性加工，形成负调控反馈回路。GSDME直接与脂肪酸合成酶（FASN）相互作用，阻断K48连接的泛素化，抑制FASN降解，驱动脂质代谢重编程和致死性肝脂肪变性。GSDME敲除消除焦亡和代谢失调，赋予对WELV感染的完全保护。临床批准的半胱天冬酶和FASN抑制剂减轻了WELV感染小鼠的肝脏病理并提高了生存率。这些发现建立了一个驱动邻空病毒发病机制的热代谢轴，强调GSDME是肝损伤的关键决定因素，也是抗病毒治疗的一个有希望的靶点。

据介绍，随着病例的增加，包括新出现的湿地病毒（WELV）在内的蜱传标准空气病毒主题引起了越来越多的公共卫生关注，但其发病机制尚不清楚。

附：英文原文

Title: Gasdermin E couples viral pyroptosis to lethal hepatic lipid accumulation

Author: Chaojie Wang, Xiaojie Zheng, Yunfa Zhang, Xing Shang, Qiaoqiao Qu, Chang Li, Xiaoai Zhang, Ningyi Jin, Wei Liu, Hao Li

Issue&Volume: 2026-07-29

Abstract: Tick-borne orthonairoviruses, including the emerging wetland virus (WELV), pose a growing public health concern as cases increase, yet their pathogenesis remains unclear. Here, we show that WELV infection causes fatal liver dysfunction in patients, characterized by elevated hepatic enzymes, triacylglycerol accumulation, and hyperinflammation. WELV induces gasdermin E (GSDME)-dependent pyroptosis in hepatocytes through mitochondrial and Fas-mediated apoptotic pathways. Viral RNA activates RIG-I/CASP3-mediated GSDME cleavage, while viral nucleoprotein undergoes CASP3-dependent processing, forming a negative regulatory feedback loop. GSDME directly interacts with fatty acid synthase (FASN) and blocks K48-linked ubiquitination to inhibit FASN degradation, driving lipid metabolic reprogramming and lethal hepatic steatosis. GSDME knockout abolishes pyroptosis and metabolic dysregulation, conferring complete protection against WELV infection. Clinically approved caspase and FASN inhibitors mitigate liver pathology and improve survival in WELV-infected mice. These findings establish a pyroptosis-metabolism axis driving orthonairovirus pathogenesis, highlighting GSDME as a critical determinant of liver injury and a promising target for antiviral therapy.

DOI: 10.1016/j.cell.2026.07.011

Source: https://www.cell.com/cell/abstract/S0092-8674(26)00809-3

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