Neutrophil extracellular traps-triggered hepatocellular senescence exacerbates lipotoxicity in non-alcoholic steatohepatitis

作者：Ming Xu, Hao Xu, Yu‐Wei Ling, Jingjing Liu, Ping Song, Zhiqiang Fang, Zhen‐Sheng Yue, Juanli Duan, Fei He, Lin Wang · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.03.015 · 被引用次数：30 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Liver Disease Diagnosis and Treatment、Liver physiology and pathology

• Neutrophil extracellular traps (NETs) accumulate in patients and mouse models with NASH. • Elimination of NETs alleviated hepatocyte senescence and hepatic steatosis in NASH mice. • Notch signaling regulates the formation of NASH-associated NETs and cellular senescence. • Notch signaling mitigates steatosis by reducing inflammatory cell infiltration,Myeloid-derived Notch signaling is anticipated to serve as a promising therapeutic target for NASH. Neutrophils are initial responders in inflammation and contribute to non-alcoholic fatty liver disease (NAFLD) progression to steatohepatitis (NASH). Neutrophil extracellular traps (NETs) are implicated in liver injury, yet their precise mechanisms in NASH progression remains unclear. This study investigates how NETs drive NASH progression by disrupting hepatocyte lipotoxicity and explore the regulatory mechanism of NETs formation and its downstream effects on liver pathology. Clinical samples from NASH patients and diet-induced NASH mice were analyzed for NET levels. NETs were pharmacologically inhibited, and senescent cells were selectively eliminated in mice. Myeloid-specific RBP-J knockout mice were generated to disrupt Notch signaling, with subsequent evaluation of NET formation, senescence markers, steatosis, fibrosis, and inflammation. NETs are elevated in NASH patients and mice, correlating with hepatocyte senescence and lipotoxicity. Pharmacological NET disruption reduced hepatocyte senescence, accompanied by attenuated s...