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

Disrupted cardiomyocyte energy metabolism underlies HFpEF. We found that cardiac succinate and GPR91 were reduced in HFpEF. In WT mice, succinate supplementation restored metabolism, improved diastolic function, and alleviated hypertrophy and fibrosis, whereas these benefits were abolished in global and cardiomyocyte-specific Gpr91 knockouts. Transcriptomics and mechanistic studies revealed that succinate–GPR91 signaling activated AMPK via Gq, enhanced NAD? production, and promoted glucose–lipid metabolic reprogramming. Thus, the succinate–GPR91 axis is essential for cardiometabolic regulation and represents a promising therapeutic target in HFpEF. Overall design: RNA-seq was performed on myocardial tissues from Gpr91fl/fl mice and cardiomyocyte-specific Gpr91 knockout mice (Myh6Cre Gpr91fl/fl) under HFpEF conditions, with or without succinate supplementation