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Abstract
Osteoarthritis (OA) is the most prevalent degenerative joint disease and is closely related to obesity. The molecular mechanisms underlying obesity-induced metabolic alterations that lead to cartilage degeneration have not been fully elucidated. Succinate, a key intermediate in the Krebs cycle, exhibits signaling functions that extend beyond its traditional metabolic role. This study demonstrates that succinate is significantly accumulated in the knee joint of obesity-associated OA. Succinate exacerbates obesity-associated cartilage degeneration through a combination of extracellular and intracellular pathways, which converge on mitochondrial dysfunction. Mechanistically, extracellular succinate activates G protein-coupled receptor succinate receptor-1 (SUCNR1), triggering mitochondrial fission and activation of the cGAS-STING pathway. Intracellular succinate reduces NADPH levels and promotes mitochondrial reactive oxygen species (mtROS) accumulation, in association with increased IDH2 succinylation. Additionally, sirtuin 5 (SIRT5) acts as an IDH2 desuccinylase and exerts a protective effect against intracellular succinate-induced cartilage degeneration. To target both intracellular and extracellular succinate, the phenylboronic acid-modified gelatin hydrogel is designed to load the SUCNR1 inhibitor 5 g and the SIRT5 agonist puerarin. This injectable ROS-responsive system targeting succinate exhibits remarkable therapeutic efficacy in vivo. These findings suggest that targeting succinate provides a novel therapeutic strategy for obesity-associated OA.
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Subjects
- Extracellular signalling molecules
- Metabolic disorders
- Post-translational modifications
Acknowledgements
We are grateful for the support and assistance provided by the Institute of Medical Innovation and Research of Peking University Third Hospital and the Department of Laboratory Animal Science of Peking University Health Science Center. We thank BioRender for assistance with the graphical abstract
Funding
This work was supported by the National Natural Science Foundation of China (#12572365, #12172011), the National Key Research and Development Program of China (#2024YFB3814700), and the Beijing Natural Science Foundation (#7252159)
Author notes
These authors contributed equally: Haofeng Hong, Longting Chen, Yiming Zhong
Authors and Affiliations
Department of Orthopedics, Peking University Third Hospital, Beijing, China
Haofeng Hong, Longting Chen, Yiming Zhong, Zihuan Yang, Zhuoxin Li, Chunli Song, Weishi Li, Wanqiong Yuan, Hua Tian & Huijie Leng
Beijing Key Laboratory of Advanced Bioadaptable Orthopedic Implants, Beijing, China
Haofeng Hong, Longting Chen, Yiming Zhong, Zihuan Yang, Zhuoxin Li, Chunli Song, Weishi Li, Wanqiong Yuan, Hua Tian & Huijie Leng
Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
Haofeng Hong, Longting Chen, Yiming Zhong, Zihuan Yang, Zhuoxin Li, Chunli Song, Weishi Li, Wanqiong Yuan, Hua Tian & Huijie Leng
Authors
- Haofeng HongView author publications
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- Longting ChenView author publications
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- Yiming ZhongView author publications
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- Zihuan YangView author publications
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- Zhuoxin LiView author publications
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- Chunli SongView author publications
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- Weishi LiView author publications
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- Wanqiong YuanView author publications
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- Hua TianView author publications
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- Huijie LengView author publications
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Cite this article
Hong, H., Chen, L., Zhong, Y. et al. Succinate exacerbates obesity-associated osteoarthritis: mitochondrial dysfunction mediated by SUCNR1 activation and succinylation modification.
Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03318-1
Received:06 May 2026
Revised:31 July 2026
Accepted:19 August 2026
Published:22 August 2026
DOI
:https://doi.org/10.1038/s41420-026-03318-1
