Short-chain fatty acids promote post-myocardial infarction cardiac repair via FFAR2-dependent suppression of osteoclast-like macrophage differentiation

Adverse cardiac remodeling leads to the development of heart failure following myocardial infarction (MI), yet the immunometabolic signals governing early infarct repair remain poorly understood. Short-chain fatty acids (SCFAs) are important immunometabolic regulators, but their relevance and mechanistic contribution to post-MI repair remain unclear. Here, we integrated clinical observations with genetic and pharmacological intervention studies to investigate the role of the SCFAs-free fatty acid receptor 2 (FFAR2) axis in post-MI repair. Circulating SCFAs levels were markedly decreased in patients with MI, and associated with more complex coronary lesions and a higher risk of major adverse cardiovascular events. In murine MI, SCFAs supplementation reduced infarct expansion, cardiomyocyte death, and cardiac rupture, and improved left-ventricular function. These benefits were lost in global and myeloid-specific Ffar2 -deficient mice, demonstrating an essential role for myeloid FFAR2 in SCFA-mediated cardioprotection. Mechanistically, SCFAs activated FFAR2-G αi signaling in macrophages to suppress RANKL–RANK-driven osteoclast-like macrophage differentiation. thereby enhancing early fibrotic stabilization, reducing cardiomyocyte apoptosis, and improving infarct healing. Pharmacological blockade of osteoclast-like macrophage activation partially rescued impaired healing and cardiac dysfunction in myeloid-specific Ffar2 -deficient mice after MI. These findings identify circulating SCFAs as clinically relevant biomarkers associated with coronary lesion complexity and adverse clinical outcomes after MI, and establish the SCFAs–FFAR2 axis as an immune-metabolic pathway that orchestrates macrophage fate and infarct healing. Targeting SCFAs–FFAR2 signaling may represent a therapeutic strategy to limit adverse post-MI remodeling and prevent heart failure.