Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERRα (estrogen-related receptor α) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined. METHODS: We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERRα. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity. RESULTS: ERRα expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERRα reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERRα overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERRα knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERRα agonist. Formononetin enhanced ERRα transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERRα occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERRα/PGC-1α complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy. CONCLUSIONS: ERRα downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERRα activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.