Zhang Jing, Wang Yu, Fan Meiyang, Guan Yanglong, Zhang Wentao, Huang Fumeng, Zhang Zhengqiang, Li Xiaomeng, Yuan Bingyu, Liu Wenbin, Geng Manman, Li Xiaowei, Xu Jing, Jiang Congshan, Zhao Wenjuan, Ye Feng, Zhu Wenhua, Meng Liesu, Lu Shemin, Holmdahl Rikard
Department of Infectious Diseases and National-Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China; Institute of Molecular and Translational Medicine and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China.
Institute of Molecular and Translational Medicine and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China.
Cell Metab. 2024 Aug 6;36(8):1745-1763.e6. doi: 10.1016/j.cmet.2024.05.008. Epub 2024 Jun 7.
Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF1 alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.
库普弗细胞（KC）自我更新受损会导致代谢功能障碍相关脂肪性肝炎（MASH）中的炎症。在此，我们确定中性粒细胞胞质因子1（NCF1）是KC中铁稳态的关键调节因子。在患有代谢功能障碍相关脂肪性肝病的人类以及MASH小鼠的肝脏巨噬细胞和树突状细胞中，NCF1上调。巨噬细胞NCF1而非树突状细胞NCF1会引发KC铁过载、铁死亡以及单核细胞来源的巨噬细胞浸润，从而加剧MASH进展。从机制上讲，巨噬细胞NCF1诱导的氧化磷脂升高会促进Toll样受体（TLR4）依赖性肝细胞铁调素的产生，导致KC铁沉积增加以及随后的KC铁死亡。重要的是，人类低功能多态性变体NCF1可减轻小鼠的KC铁死亡和MASH。总之，巨噬细胞NCF1通过氧化磷脂损害KC中的铁稳态，触发肝细胞铁调素释放和MASH中的KC铁死亡，突出了NCF1作为改善KC命运和限制MASH进展的治疗靶点。
