上海临港实验室取得一项新突破。他们报道了AMPK通过线粒体自噬诱导的代谢重编程维持肝星状细胞的激活。2025年9月4日，国际知名学术期刊《分子细胞生物学报》发表了这一成果。

研究组发现，代谢功能障碍相关的脂肪性肝炎患者和接受四氯化碳（CCl4）或胆管结桥（BDL）治疗的小鼠的肝组织中，造血干细胞中AMPK的磷酸化水平上调。在CCl4或BDL模型中，HSCs特异性缺失AMPK的两个催化α-亚基可减轻肝纤维化。体外分析表明，AMPK在各种促纤维化刺激下促进HSC活化。AMPK α-缺陷造血干细胞的活化因线粒体氧化磷酸化降低而受损，但在线粒体自噬诱导剂雷帕霉素治疗后恢复。从机制上讲，AMPK-ULK1和AMPK-Raptor通路都有助于线粒体自噬通路和线粒体质量的维持。这些发现为AMPK-线粒体自噬信号在确保HSC激活过程中线粒体健康和充足能量供应中的关键作用提供了直接证据。在本研究中，AMPK在激活前在HSC中被调节，这与之前的研究不同，并为AMPK在HSC激活的不同阶段中的作用提供了新的见解。

据悉，肝星状细胞（HSCs）的激活是肝纤维化的核心过程，其特征是从静止状态转分化为纤维化表型。造血干细胞的代谢重编程在这一过程中发挥了重要作用，以满足肌成纤维造血干细胞对细胞外基质合成、迁移和增殖等多种功能的高能量需求。AMP活化蛋白激酶（AMPK）是细胞内能量稳态的守门人，但其在HSCs活化和肝纤维化进展中的作用尚不清楚。

附：英文原文

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

Author: Wang, Hanmin, Wang, Guanzhen, Yin, Tao, Li, Hao, Wang, Hanlin, Shao, Yikai, Li, Yuanyuan, Hua, Rong, Li, Jia, Zang, Yi

Issue&Volume: 2025-09-04

Abstract: 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 when challenged with 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 supply during HSC activation. In this study, AMPK was modulated in HSCs prior to activation, which is distinguished from previous investigations and thus provides new insights into the role of AMPK during distinct phases of HSC activation.

DOI: 10.1093/jmcb/mjaf030

Source: https://dx.doi.org/10.1093/jmcb/mjaf030