Cardiac Benefits of Urolithin A (UA) via Mitophagy-mediated Mitochondrial Health Improvement in Heart Failure with Preserved Ejection Fraction (HFpEF)

Abstract

Heart failure with preserved ejection fraction (HFpEF) is marked by diastolic dysfunction and systemic metabolic–inflammatory stress that impair mitochondrial quality control (MQC) and mitophagy. Urolithin A (UA), a gut microbiome–derived postbiotic, is known to enhance mitochondrial health through mitophagy activation. Here, we evaluated whether UA improves cardiac remodeling and function in a two-hit HFpEF mouse model and complementary cardiomyocyte systems. UA treatment attenuated pathological remodeling and fibrosis, improved diastolic parameters, and restored mitochondrial ultrastructure and respiration. Mechanistically, UA reactivated the PINK1–Parkin mitophagy pathway and restored mitophagic flux, as evidenced by increased LC3-II with reduced p62, enhanced mitolysosome formation in mt-Keima assays, and BafA1-sensitive accumulation patterns indicative of lysosome-dependent clearance. These findings support that UA improves cardiac function by normalizing mitochondrial turnover through restored PINK–Parkin–mediated mitophagy. Metagenomics–lipidomics integration demonstrated that UA attenuates ceramide biosynthesis by reducing both the abundance of ceramide-producing microbiota and the expression of ceramide-associated KO pathways, with Bacteroidetes emerging as the dominant taxon linked to ceramide metabolic output. snRNA-seq further showed that UA suppresses HFpEF-associated fibrosis programs and restores cardiomyocytes toward a more normal contractile state. Collectively, UA emerges as a mitochondria-targeted therapeutic candidate that restores MQC, mitigates metabolic–fibrotic stress, and promotes cardiomyocyte recovery in HFpEF, underscoring the translational value of integrating functional and molecular readouts.