Hepatic stellate cells (HSCs) secrete extracellular matrix for collagen deposition, contributing to liver fibrosis. Ferroptosis is a novel type of programmed cell death induced by iron overload-dependent lipid peroxidation. Regulation of ferroptosis in hepatic stellate cells (HSCs) may have therapeutic potential for liver fibrosis. Here, we found that Maf bZIP transcription factor G (MafG) was upregulated in human and murine liver fibrosis. Interestingly, MafG knockdown increased HSCs ferroptosis, while MafG overexpression conferred resistance of HSCs to ferroptosis. Mechanistically, MafG physically interacted with non-muscle myosin heavy chain IIa (MYH9) to transcriptionally activate lipocalin 2 (LCN2) expression, a known suppressor for ferroptosis. Site-directed mutations of MARE motif blocked the binding of MafG to LCN2 promoter. Re-expression of LCN2 in MafG knockdown HSCs restored resistance to ferroptosis. In bile duct ligation (BDL)-induced mice model, we found that treatment with erastin alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific knowdown MafG based on adeno-associated virus 6 (AAV-6) improved erastin-induced HSC ferroptosis and alleviation of liver fibrosis. Taken together, MafG inhibited HSCs ferroptosis to promote liver fibrosis through transcriptionally activating LCN2 expression. These results suggest that MafG/MYH9-LCN2 signaling pathway could be a novel targets for the treatment of liver fibrosis.

肝星状细胞（HSC）分泌细胞外基质用于胶原沉积，导致肝纤维化。铁死亡是一种由铁超载依赖性脂质过氧化诱导的新型程序性细胞死亡。肝星状细胞（HSC）铁死亡的调节可能具有治疗肝纤维化的潜力。在这里，我们发现 Maf bZIP 转录因子 G (MafG) 在人和小鼠肝纤维化中表达上调。有趣的是，MafG 敲除增加了 HSC 铁死亡，而 MafG 过表达则赋予 HSC 对铁死亡的抵抗力。从机制上讲，MafG 与非肌肉肌球蛋白重链 IIa (MYH9) 发生物理相互作用，以转录激活脂质运载蛋白 2 (LCN2) 的表达，脂质运载蛋白 2 (LCN2) 是一种已知的铁死亡抑制剂。 MARE 基序的定点突变阻断了 MafG 与 LCN2 启动子的结合。 MafG 敲低 HSC 中 LCN2 的重新表达恢复了对铁死亡的抵抗力。在胆管结扎 (BDL) 诱导的小鼠模型中，我们发现用erastin治疗可通过诱导HSC铁死亡来减轻小鼠肝纤维化。基于腺相关病毒 6 (AAV-6) 的 HSC 特异性知识 MafG 可改善erastin 诱导的 HSC 铁死亡并减轻肝纤维化。综上所述，MafG 通过转录激活 LCN2 表达来抑制 HSC 铁死亡，从而促进肝纤维化。这些结果表明MafG/MYH9-LCN2信号通路可能成为治疗肝纤维化的新靶点。