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已发表论文
二甲双胍通过激活 AMPK/Drp1 通路调节线粒体动力学减轻骨关节炎进展
Authors Yang Y, Zhou H, Yang J, Li F, Hu Q, Jia Y , Huang W , Qin L, Zhou Y
Received 30 May 2025
Accepted for publication 22 December 2025
Published 2 February 2026 Volume 2026:19 540176
DOI https://doi.org/10.2147/JIR.S540176
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Ujjwol Risal
Yaji Yang,1– 4,* Haotian Zhou,2– 4,* Jianye Yang,2– 5 Feilong Li,2– 4,6 Qianshui Hu,2– 4 Ying Jia,2– 4 Wei Huang,2– 4 Leilei Qin,2– 4 Yu Zhou1– 4
1Orthopedic Hospital, Chongqing University of Chinese Medicine, Chongqing, 400012, People’s Republic of China; 2Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 4Orthopaedic Research Laboratory, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 5Orthopedics Department, Chongqing university Fuling hospital, Chongqing, 408107, People’s Republic of China; 6Department of Orthopaedics, The People’s Hospital of Dazu, Chongqing, 402360, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Leilei Qin, Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Email 253505921@qq.com Yu Zhou, Orthopedic Hospital, Chonqqing University of Chinese Medicine, Chongqing, 400012, People’s Republic of China, Email zyhenry123@163.com
Background: Osteoarthritis (OA) is a chronic degenerative disease primarily characterized by articular cartilage degradation and chondrocyte dysfunction. Mitochondrial impairment and oxidative stress in chondrocytes are pivotal contributors to OA pathogenesis. Emerging evidence suggests that metformin, beyond its role in glucose regulation, exhibits antioxidative and anti-inflammatory properties via activation of AMP-activated protein kinase (AMPK). Nonetheless, how metformin regulates mitochondrial dynamics and autophagy in OA remains to be fully elucidated.
Methods: A mouse anterior cruciate ligament transection (ACLT) model and an IL-1β-induced oxidative stress model in human chondrocytes were established. Following metformin administration, a comprehensive assessment was conducted using histological staining, immunohistochemistry, Western blotting, flow cytometry, confocal microscopy, and AMPK siRNA transfection to evaluate the effects of metformin on mitochondrial function, autophagic activity, and oxidative stress in chondrocytes.
Results: Metformin markedly improved articular cartilage architecture in ACLT mice and enhanced the stability of the cartilage matrix. It activated AMPK signaling in chondrocytes while suppressing Dynamin-related protein 1 (Drp1) phosphorylation at Ser637, thereby promoting mitochondrial fission and mitophagy. By reducing reactive oxygen species accumulation, restoring mitochondrial membrane potential, and inhibiting NOD-like receptor thermal protein domain associated protein 3 inflammasome activation, metformin effectively mitigated oxidative stress in chondrocytes. AMPK siRNA experiments further demonstrated that the AMPK/Drp1 axis is pivotal for metformin-induced mitochondrial protection and promotion of chondrocyte proliferation.
Conclusion: This study demonstrates that metformin delays osteoarthritis progression by activating the AMPK/Drp1 pathway to modulate mitochondrial fission and mitophagy, attenuate oxidative stress, and restore chondrocyte function. These findings provide novel mechanistic insight into the therapeutic potential of metformin in osteoarthritis and highlight mitochondrial dynamics as a promising target for future OA interventions.
Keywords: AMPK, Drp1, metformin, mitochondrial fission, mitophagy, osteoarthritis
1Orthopedic Hospital, Chongqing University of Chinese Medicine, Chongqing, 400012, People’s Republic of China; 2Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 4Orthopaedic Research Laboratory, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 5Orthopedics Department, Chongqing university Fuling hospital, Chongqing, 408107, People’s Republic of China; 6Department of Orthopaedics, The People’s Hospital of Dazu, Chongqing, 402360, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Leilei Qin, Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China, Email 253505921@qq.com Yu Zhou, Orthopedic Hospital, Chonqqing University of Chinese Medicine, Chongqing, 400012, People’s Republic of China, Email zyhenry123@163.com
Background: Osteoarthritis (OA) is a chronic degenerative disease primarily characterized by articular cartilage degradation and chondrocyte dysfunction. Mitochondrial impairment and oxidative stress in chondrocytes are pivotal contributors to OA pathogenesis. Emerging evidence suggests that metformin, beyond its role in glucose regulation, exhibits antioxidative and anti-inflammatory properties via activation of AMP-activated protein kinase (AMPK). Nonetheless, how metformin regulates mitochondrial dynamics and autophagy in OA remains to be fully elucidated.
Methods: A mouse anterior cruciate ligament transection (ACLT) model and an IL-1β-induced oxidative stress model in human chondrocytes were established. Following metformin administration, a comprehensive assessment was conducted using histological staining, immunohistochemistry, Western blotting, flow cytometry, confocal microscopy, and AMPK siRNA transfection to evaluate the effects of metformin on mitochondrial function, autophagic activity, and oxidative stress in chondrocytes.
Results: Metformin markedly improved articular cartilage architecture in ACLT mice and enhanced the stability of the cartilage matrix. It activated AMPK signaling in chondrocytes while suppressing Dynamin-related protein 1 (Drp1) phosphorylation at Ser637, thereby promoting mitochondrial fission and mitophagy. By reducing reactive oxygen species accumulation, restoring mitochondrial membrane potential, and inhibiting NOD-like receptor thermal protein domain associated protein 3 inflammasome activation, metformin effectively mitigated oxidative stress in chondrocytes. AMPK siRNA experiments further demonstrated that the AMPK/Drp1 axis is pivotal for metformin-induced mitochondrial protection and promotion of chondrocyte proliferation.
Conclusion: This study demonstrates that metformin delays osteoarthritis progression by activating the AMPK/Drp1 pathway to modulate mitochondrial fission and mitophagy, attenuate oxidative stress, and restore chondrocyte function. These findings provide novel mechanistic insight into the therapeutic potential of metformin in osteoarthritis and highlight mitochondrial dynamics as a promising target for future OA interventions.
Keywords: AMPK, Drp1, metformin, mitochondrial fission, mitophagy, osteoarthritis