Quercetin alleviates LPS/iE-DAP-induced liver injury by suppressing ferroptosis via regulating ferritinophagy and intracellular iron efflux

作者：Hongzhu Zhang, Huimin Shi, Xuerui Li, Shendong Zhou, Xiaokun Song, Nana Ma, Meijuan Meng, Guangjun Chang, Xiangzhen Shen · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103557 · 被引用次数：36 · 研究领域：Ferroptosis and cancer prognosis、Iron Metabolism and Disorders、Trace Elements in Health

Ruminal dysbiosis-induced liver injury is prevalent in dairy cows, yet its underlying mechanisms remain incompletely understood. Ferroptosis, a newly identified form of programmed cell death distinct from apoptosis and necrosis, has been implicated in various liver diseases by emerging studies. In the present study, lipopolysaccharide (LPS) and γ-D-glutamyl‐meso‐diaminopimelic acid (iE-DAP) were employed to establish in vitro and in vivo models of liver injury using bovine hepatocytes and mice, respectively. It was observed that noncytotoxic iE-DAP alone did not influence lipid peroxidation or GPX4, but exacerbated LPS-induced ferroptosis and hepatocyte injury. Notably, co-treatment with LPS and iE-DAP (LPS/iE-DAP)-induced hepatocyte injury was mitigated by intervention with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, the activated IL-6/STAT3 signaling pathway was found to mediate LPS/iE-DAP-induced ferroptosis. Suppression of IL-6/STAT3, either through IL6 and STAT3 knockdown or pharmacological intervention, reduced Fe 2+ accumulation and alleviated ferroptotic cell death. Further investigations identified that IL-6/STAT3 signaling enhanced ferritinophagy and impaired iron export. Either disrupting ferritinophagy by knocking down NCOA4 or restoring iron export via HAMP knockdown relieved intracellular iron overload and inhibited ferroptosis. Specifically, LPS/iE-DAP treatment increased the interaction between hepcidin and ferroportin, promoting ferropor...