AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming

作者：Hanming Wang, Guanzhen Wang, Tao Yin, Hao Li, Hanlin Wang, Yikai Shao, Yuanyuan Li, Rong Hua, Jia Li, Yi Zang · 发表于：Journal of Molecular Cell Biology · 年份：2025 · DOI：10.1093/jmcb/mjaf030 · 被引用次数：5 · 研究领域：Liver Disease Diagnosis and Treatment、Liver physiology and pathology、Pancreatic function and diabetes

The activation of hepatic stellate cells (HSCs), characterized by transdifferentiation from a quiescent state to a fibrogenic phenotype, is a core process of liver fibrosis. The metabolic reprogramming of HSCs plays a major role in this process to meet the high energy demands of myofibroblastic HSCs with multiple functions, such as extracellular matrix synthesis, migration, and proliferation. AMP-activated protein kinase (AMPK) is a gatekeeper of intracellular energy homeostasis, but its role in the activation of HSCs and the progression of liver fibrosis remains unclear. Here, we found that the phosphorylation of AMPK in HSCs was upregulated in liver tissues from metabolic dysfunction-associated steatohepatitis patients and from mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). HSC-specific deletion of two catalytic α-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model. In vitro analysis demonstrated that AMPK promoted HSC activation upon various profibrogenic stimuli. The activation of AMPKα-deficient HSCs was impaired due to the decreased mitochondrial oxidative phosphorylation but restored after treatment with the mitophagy inducer rapamycin. Mechanistically, both the AMPK-ULK1 and AMPK-Raptor pathways contribute to the maintenance of the mitophagy pathway and mitochondrial quality. These findings provide direct evidence of the crucial role of AMPK-mitophagy signaling in ensuring mitochondrial health and sufficient energy sup...