Baicalein Alleviates Cardiomyocyte Hypoxia Injury via ESR1‐Dependent Modulation of BAX/BCL‐XL Balance

ABSTRACT Background Hypoxia is a core pathological factor in myocardial injury and is involved in the development of various cardiovascular diseases. Although baicalein shows cardiovascular protective potential, its mechanism against hypoxic injury remains unclear. Methods H9c2 cardiomyocytes were exposed to sodium sulfite to establish a chemical hypoxia model. Network pharmacology, molecular docking, molecular dynamics simulation, and molecular biology assays were employed to predict the core target and investigate the underlying mechanism. Results Network pharmacology identified ESR1 as a core target, with stable binding to baicalein confirmed by molecular docking and dynamics simulations. Baicalein alleviated hypoxia‐induced oxidative stress by elevating key antioxidant markers and reducing malondialdehyde levels. It also ameliorated energy metabolism disorders, reduced lactate dehydrogenase release, suppressed reactive oxygen species production, and decreased cell apoptosis. Furthermore, baicalein upregulated hypoxia‐suppressed ESR1 protein expression and enhanced its co‑localization with the antiapoptotic protein BCL‐XL. The cytoprotective effects were abolished by the ESR1 inhibitor fulvestrant. Conclusion These findings demonstrate that baicalein protects cardiomyocytes against hypoxic injury through an ESR1‑dependent mechanism by modulating the BCL‑XL/BAX apoptotic balance, mitigating oxidative stress, and improving energy metabolism.