Qi-Blood Harmony Formula mediates post-MI cardioprotection via FTO-driven dual modulation of energy metabolism and fibrosis: a multi-omics validation

Myocardial infarction (MI) remains a leading cause of death worldwide. Persistent myocardial fibrosis and dysregulated energy metabolism following MI contribute to adverse cardiac remodeling and are associated with poor clinical prognosis. Currently, no guideline-recommended therapy provides effective long-term intervention simultaneously targeting both of these core pathological mechanisms. The Qi-Blood Harmony Formula (QBHF), a classical Chinese herbal prescription, has demonstrated cardioprotective potential on attenuating fibrosis, preserving mitochondrial integrity, and restoring myocardial ATP levels in MI, yet its underlying mechanisms and therapeutic targets remain unclear. Using an integrated multi-omics approach in a mouse MI model, we showed that QBHF reactivated genes related to energy metabolism while suppressing pro-fibrotic pathways, as revealed by bulk RNA-sequencing. Non-targeted metabolomics further confirmed its efficacy in counteracting metabolic dysregulation. Single-nucleus RNA sequencing revealed that QBHF altered cardiac cellular composition characterized by reducing a major profibrotic fibroblast subpopulation and expanding a metabolically robust cardiomyocyte subset. Integrative multi-omics analysis identified the fat mass and obesity-associated protein (FTO) as a central regulatory hub modulated by QBHF across bulk heart tissue, fibroblasts, and cardiomyocytes. Crucially, heterozygous knockout of FTO in mice abolished QBHF-mediated improvements in cardiac fibrosis, ATP level and heart function. Consistently, FTO knockdown in cardiomyocytes blunted QBHF-induced ATP restoration. Together, these findings demonstrate that QBHF confers post-MI cardioprotection via FTO-driven dual modulation of energy metabolism and fibrosis. Our findings highlight FTO as a promising therapeutic target and provide novel mechanistic insights into traditional Chinese medicine-based interventions for post-MI injury.