Objective: Cardiovascular diseases remain a major cause of global mortality, and myocardial ischemia–reperfusion (IR) injury contributes substantially to cardiac damage. Urolithin A (UA), a gut-derived metabolite of dietary ellagitannins, regulates autophagy, apoptosis, and inflammation. This study evaluated UA in an in vitro hypoxia–reperfusion (HR) model using H9C2 cardiomyocytes.
Materials and Methods: Cell viability was assessed by MTT assay across multiple UA concentrations. Real-time PCR quantified the expression of genes associated with autophagy, apoptosis, and inflammation.
Results: UA caused concentration-dependent cytotoxicity, with greater sensitivity under normoxia (IC₅₀ = 25.4 µM) than HR conditions (IC₅₀ = 70.1 µM). Under HR, UA increased LC3, TFEB, LAMP2, and BECN1 expression while reducing P62, consistent with enhanced autophagic flux. Bax and BCL2 were both downregulated, and the decreased Bax/BCL2 ratio indicated a net anti-apoptotic effect. However, UA also increased IL-1β, IL-6, and TNF-α expression, demonstrating a concurrent pro-inflammatory response.
Conclusion: UA enhances autophagy and suppresses apoptosis in HR-stressed cardiomyocytes but simultaneously promotes inflammatory signaling. These context-dependent effects support its potential as a modulator of IR injury while underscoring the need for protein-level validation, dose optimization, temporal analysis, and in vivo studies before therapeutic application.