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-Gαi 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.