Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD⁺ production to alleviate HFpEF

Abstract Background: Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. Beyond its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate–GPR91 signaling in HFpEF pathogenesis remain largely unknown. Methods: HFpEF models were established in wild-type, global GPR91 knockout, and cardiomyocyte-specific GPR91 knockout mice with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify succinate–GPR91–dependent signaling pathways. Mechanistic studies in isolated cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Rescue experiments were further carried out to confirm the functional relevance of succinate–GPR91 signaling in cardiomyocyte metabolism and HFpEF progression. Results: Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in wild-type (WT) HFpEF mice, but these protective effects were lost in both global Gpr91⁻/⁻ and cardiomyocyte-specific Gpr91ΔCM knockouts. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose–lipid metabolism and NAD⁺ biosynthesis in Gpr91fl/fl but not in Gpr91ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD⁺ production via Gq-mediated signaling, thereby promoting metabolic reprogramming. Conclusion: These findings identify the succinate–GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.