Metabolite sensing in cardiometabolic HFpEF: mechanisms and therapeutic perspectives

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a prevalent subtype driven by obesity and diabetes. While systemic inflammation and myocardial fibrosis are known hallmarks, the mechanisms linking metabolic disturbances to cardiac remodeling remain poorly understood. Previous studies have often regarded metabolic abnormalities as passive byproducts of the disease process, neglecting the active regulatory role of metabolites themselves as bioactive signaling molecules. This review elucidates the molecular mechanisms of cardiometabolic HFpEF through the perspective of metabolite sensing. We elaborated on how different cell types decode changes in lipid metabolites, amino acids, TCA cycle intermediates, and gut microbiota-derived signals through specific sensors. These sensing cascades drive adipose tissue dysfunction, immunometabolic abnormalities, impaired myocardial metabolic flexibility, and fibrosis. Additionally, we focused on how intermediate metabolites directly serve as substrates for epigenetic and post-translational modifications, converting transient metabolic stress into a persistent pathological metabolic memory, and briefly discussed sex differences in metabolic sensing. Therapeutically, while SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone provide clinical benefits by restoring metabolic-cardiac homeostasis, targeting upstream metabolite-sensing pathways, such as epigenetic modifier regulators JQ1 and RVX-208 and gut microbiota metabolites, shows great potential. Ultimately, understanding how metabolites are sensed and translated into pathological signals is a key breakthrough for achieving precision therapy in cardiometabolic HFpEF.