Academic Journal
AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming.
| Title: | AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming. |
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| Authors: | Wang H; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Wang G; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Yin T; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; Lingang Laboratory, Shanghai 200031, China., Li H; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China., Wang H; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China., Shao Y; Center for Obesity and Hernia Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China.; Department of General Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China.; National Center for Neurological Disorders, Huashan Hospital of Fudan University, Shanghai 200040, China., Li Y; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China., Hua R; Center for Obesity and Hernia Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China.; Department of General Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China.; National Center for Neurological Disorders, Huashan Hospital of Fudan University, Shanghai 200040, China., Li J; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.; University of Chinese Academy of Sciences, Beijing 100049, China.; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China., Zang Y; Lingang Laboratory, Shanghai 200031, China. |
| Source: | Journal of molecular cell biology [J Mol Cell Biol] 2026 Feb 13; Vol. 17 (7). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 101503669 Publication Model: Print Cited Medium: Internet ISSN: 1759-4685 (Electronic) Linking ISSN: 17594685 NLM ISO Abbreviation: J Mol Cell Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Cary, NC : Oxford University Press |
| MeSH Terms: | Hepatic Stellate Cells*/metabolism , Hepatic Stellate Cells*/pathology , AMP-Activated Protein Kinases*/metabolism , AMP-Activated Protein Kinases*/genetics , Mitophagy* , Cellular Reprogramming*, Liver Cirrhosis/pathology ; Liver Cirrhosis/metabolism ; Mitochondria/metabolism ; Animals ; Mice ; Humans ; Mice, Inbred C57BL ; Male ; Carbon Tetrachloride ; Signal Transduction ; Phosphorylation ; Metabolic Reprogramming |
| 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 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 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. (© The Author(s) (2025). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.) |
| Grant Information: | 82130099 National Natural Science Foundation of China; 2019ZX09201001-003-010 Key New Drug Creation and Manufacturing Program of China; CASIMM0120225006-2 Shanghai Institute of Materia Medica; tstp0648 Taishan Scholar Foundation of Shandong Province; ZR2024QC378 Natural Science Foundation of Shandong Province |
| Contributed Indexing: | Keywords: AMP-activated protein kinase (AMPK); hepatic stellate cells; liver fibrosis; mitochondria; mitophagy |
| Substance Nomenclature: | EC 2.7.11.31 (AMP-Activated Protein Kinases) CL2T97X0V0 (Carbon Tetrachloride) |
| Entry Date(s): | Date Created: 20250904 Date Completed: 20260224 Latest Revision: 20260226 |
| Update Code: | 20260226 |
| PubMed Central ID: | PMC12929916 |
| DOI: | 10.1093/jmcb/mjaf030 |
| PMID: | 40905731 |
| Database: | MEDLINE |
| ISSN: | 1759-4685 |
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| DOI: | 10.1093/jmcb/mjaf030 |