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

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. In addition to 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 incompletely understood. HFpEF models were established in wild-type (WT), global GPR91 knockout (Gpr91 -/- ), and cardiomyocyte-specific GPR91 knockout (Gpr91 ΔCM ) 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 pathways regulated by succinate–GPR91 signaling. Mechanistic studies in human AC16 cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Additionally, rescue experiments were performed to confirm the functional relevance of succinate–GPR91 signaling in cardiomyocyte metabolism and HFpEF progression. 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 WT HFpEF mice, whereas these protective effects were abolished in both Gpr91 -/- and Gpr91 ΔCM mice. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose–lipid metabolism and NAD + biosynthesis in Gpr91 fl/fl but not in Gpr91 ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD + production via Gq-mediated signaling, thereby promoting cardiomyocyte metabolic reprogramming. These findings identify the succinate–GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.