The AMPK signaling pathway in cell metabolism and human diseases
8 affiliations
- 1The First Affiliated Hospital of Soochow University, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China
- 2Biomedical Basic Research Center of Jiangsu, Soochow University, Suzhou, China
- 3Department of Gynecological Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- 4Department of Rheumatology and Immunology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
- 5Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- 6The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- 7Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China
- 8Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China
Abstract
Adenosine 5’-monophosphate−activated protein kinase (AMPK), a highly conserved energy-sensing kinase, plays a central role in maintaining cellular metabolic homeostasis, such as glucose/lipid metabolism, mitochondrial biogenesis, and autophagy, to counteract energetic stress. Beyond the canonical adenylate-dependent activation of AMPK by sensing the ATP:AMP/ADP ratio, emerging evidence reveals noncanonical activation mechanisms. Proper AMPK signaling is essential for physiological functions, whereas its dysregulation underlies various pathologies, including metabolic diseases, immune disorders, and cancer. This review systematically recapitulates the historical background and landmark discoveries of the AMPK field, including the discovery of AMPK, the structure of AMPK complex, upstream regulators and downstream substrates, and the transcriptional/posttranscriptional and posttranslational regulatory mechanisms. Furthermore, we delineate its roles in maintaining metabolic equilibrium, mitochondrial integrity, and immune competence across organ systems and highlight how dysregulated AMPK activity contributes to pathological diseases, encompassing alterations in its expression levels, intrinsic kinase activity, subcellular localization or upstream regulatory signaling cascades. Specifically, we focus on knock-in or knockout mouse models utilized to study AMPK-associated human diseases and the translational potential of AMPK-targeting agonists or antagonists across diverse pathological conditions. A deep understanding of the multidimensional regulatory network of AMPK and mechanistic insights with therapeutic innovations that we provide with this review will help address the challenges of complex metabolic diseases.
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BibTeX
@article{zhang2026ampk,
title = {{The AMPK signaling pathway in cell metabolism and human diseases}},
author = {Zhengkui Zhang and Yuanzhuo Gu and HongChao He and Shilei Qiao and Yifan Shao and Xianming Long and Jun Huang and Long Zhang and Fangfang Zhou},
journal = {Signal Transduction and Targeted Therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02790-6},
url = {https://doi.org/10.1038/s41392-026-02790-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The AMPK signaling pathway in cell metabolism and human diseases
AU - Zhengkui Zhang
AU - Yuanzhuo Gu
AU - HongChao He
AU - Shilei Qiao
AU - Yifan Shao
AU - Xianming Long
AU - Jun Huang
AU - Long Zhang
AU - Fangfang Zhou
PY - 2026
DA - 2026/10/27
JO - Signal Transduction and Targeted Therapy
DO - 10.1038/s41392-026-02790-6
UR - https://doi.org/10.1038/s41392-026-02790-6
AB - Adenosine 5’-monophosphate−activated protein kinase (AMPK), a highly conserved energy-sensing kinase, plays a central role in maintaining cellular metabolic homeostasis, such as glucose/lipid metabolism, mitochondrial biogenesis, and autophagy, to counteract energetic stress. Beyond the canonical adenylate-dependent activation of AMPK by sensing the ATP:AMP/ADP ratio, emerging evidence reveals noncanonical activation mechanisms. Proper AMPK signaling is essential for physiological functions, whereas its dysregulation underlies various pathologies, including metabolic diseases, immune disorders, and cancer. This review systematically recapitulates the historical background and landmark discoveries of the AMPK field, including the discovery of AMPK, the structure of AMPK complex, upstream regulators and downstream substrates, and the transcriptional/posttranscriptional and posttranslational regulatory mechanisms. Furthermore, we delineate its roles in maintaining metabolic equilibrium, mitochondrial integrity, and immune competence across organ systems and highlight how dysregulated AMPK activity contributes to pathological diseases, encompassing alterations in its expression levels, intrinsic kinase activity, subcellular localization or upstream regulatory signaling cascades. Specifically, we focus on knock-in or knockout mouse models utilized to study AMPK-associated human diseases and the translational potential of AMPK-targeting agonists or antagonists across diverse pathological conditions. A deep understanding of the multidimensional regulatory network of AMPK and mechanistic insights with therapeutic innovations that we provide with this review will help address the challenges of complex metabolic diseases.
SN - 2095-9907
SN - 2059-3635
ER -