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SIRT5 Ameliorates Cardiac Fibrosis via PCK2 Desuccinylation-Mediated Metabolic Reprogramming in Cardiac Fibroblasts
Maoxiong Wu1,2,3, Jing Tan4, Weibin Zhou1,2,3
1Department of Cardiology (M.W., W.Z., Z.Z., Q.G., Yangwei Cai, G.L., Z. Cao, C.Z., Y.Z., Z. Chen, Q.Q., J.W., H.Z., Yangxin Chen), Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
Circulation
|April 23, 2026
Summary
SIRT5 (sirtuin 5) protects against cardiac fibrosis by preventing metabolic reprogramming in cardiac fibroblasts. Reduced SIRT5 levels exacerbate heart failure, while its presence maintains cardiac function.
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Molecular Cardiology
Background:
- Sirtuin 5 (SIRT5) is implicated in cardiac metabolism and function.
- The role of SIRT5 in cardiac fibroblast (CFB) metabolism and fibrosis is not well understood.
Purpose of the Study:
- To investigate the role of SIRT5 in cardiac fibroblast activation and fibrosis.
- To elucidate the molecular mechanisms underlying SIRT5's function in the failing heart.
Main Methods:
- Assessed SIRT5 expression in human and mouse heart failure models.
- Utilized CFB-specific Sirt5 knockout and overexpression mouse models.
- Examined the impact of PCK2 succinylation at Lys489 on SIRT5-mediated fibrosis.
Main Results:
- SIRT5 expression is decreased in heart failure CFBs, correlating with fibrosis severity.
- Sirt5 deficiency exacerbates cardiac dysfunction and fibrosis, while overexpression attenuates it.
- SIRT5 desuccinylates PCK2 at Lys489, inhibiting CFB activation and metabolic reprogramming.
Conclusions:
- SIRT5 plays a protective role against cardiac fibrosis.
- Desuccinylation of PCK2 at Lys489 by SIRT5 is a key mechanism in preventing CFB activation and metabolic shifts.
