Abstract
Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using SUCNR1–/– mice, we establish that succinate signaling through SUCNR1/GPR91 promotes PKM2 succinylation and dimerization, creating a profibrotic network associated with aging-related diastolic dysfunction. Nuclear translocation of dimeric PKM2 enables fibroblast activation through HIF-1α binding, enhancing DNA-binding affinity and upregulating fibrogenic genes. Metformin treatment suppresses fibroblast activation by reducing succinate accumulation, revealing therapeutic potential for mitigating age-related cardiac fibrosis and diastolic dysfunction. Our findings identify metabolic dysregulation as a critical target and characterize a succinate-PKM2 signaling axis whose interruption may attenuate cardiac aging.
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All data supporting the findings of this study are included in the article and its Supplementary Information. The source data underlying the graphs are available in Supplementary Data files provided with this paper.
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Acknowledgements
This work was supported by the China National Postdoctoral Program for Innovative Talents (BX2021198 to Z.W.), China Postdoctoral Science Foundation (2022M712215 to Z.W.), Beijing Postdoctoral Research Foundation (2022-ZZ-009 to Z.W.), National Natural Science Foundation of China (32100939 to Z.W.), Hebei Natural Science Foundation (C2022104004 to Z.W.), Hebei Medical Science Research Project (20221909 to Z.W., 20221907 to X. Zhang and 20232039 to Z.P.), Military Traditional Chinese Medicine Service Capacity Cultivation and Enhancement Project(2023ZY013 X.C.), Military Logistics Research Project (ZLJ22J027 to X.C.), Army Medical Research Project (2023JS04 to Z.L.), Chengdu Medical College Clinical Research Fund Project (2022LHJYZD-01 to Z.J.), Open Research Topic of Sichuan Provincial Clinical Research Center for Geriatric Medicine (2022LHTD-01 to Z.J.), Chengdu Medical College Clinical Research Fund Project (2021LHJYZD-03 to Z.J.). We gratefully acknowledge Professor Xuebin Cao, our co-corresponding author, for covering the Article Processing Charges (APC).
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Z. Wang, D. Zhou, and X. Cao led the study conception and design; H. Shi and T. Sun participated in the design process; Z. Wang performed most of the experiments and performed the data analysis; Z. Zhang, Z. Ping, S. Yang, Y. Li, T. Jiang, and X. Zheng performed some experiments; Q. Zhang, Z. Liu, X. Zhang, Z. Jiang, L. Deng, H. Sun, and B. Wu analyzed and interpreted data from experiments; Z. Wang wrote the paper; all authors discussed the results and commented on the manuscript. Z. Wang ordered SUCNR1–/– mice from Cyagen Biosciences Inc. and expanded the colony to a scale sufficient for the present study as well as other fibrosis-related experiments requiring this mouse model within the laboratory.
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Wang, Z., Zhang, Z., Ping, Z. et al. Succinate-driven PKM2 succinylation and dimerization accelerates age-associated cardiac fibrosis. Commun Biol (2025). https://doi.org/10.1038/s42003-025-09337-5
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DOI: https://doi.org/10.1038/s42003-025-09337-5
