Biochanin A mitigates colitis by inhibiting ferroptosis-mediated intestinal barrier dysfunction, oxidative stress, and inflammation via the JAK2/STAT3 signaling pathway.

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by intestinal barrier dysfunction, oxidative stress, and inflammation. Biochanin A (BCA) is a natural flavonoid found in various plants, known for its anti-inflammatory, antioxidant, and anticancer properties, while its therapeutic role in UC and potential mechanism remains unexplored.

Objective: To explores the therapeutic potential of BCA in alleviating UC, focusing on its effects on ferroptosis and the JAK2/STAT3 signaling pathway.

Methods: The BCA's therapeutic effects on Dextran sulfate sodium (DSS)-induced colitis model in C57BL/6J mice was investigated. Subsequently, a comprehensive range of techniques was performed to investigate the impact of BCA on intestinal barrier integrity, oxidative stress, inflammation. Besides, the RNA sequencing was performed to explore the potential mechanism. The role of ferroptosis inhibition in BCA's effects in vitro and in vivo was explored by co-treating with the ferroptosis activator Erastin.

Results: Treatment of colitis mice with BCA significantly improved DAI scores and histopathological damage scores, reduced oxidative stress, enhanced intestinal barrier function, and suppress inflammatory responses. RNA sequencing result found that BCA could lead to the inhibition of ferroptosis in mice colon tissue. Moreover, erastin co-treatment negated BCA's effects in vitro and vivo. Mechanistically, BCA exerts these effects by suppressing the JAK2/STAT3 pathway, which plays a pivotal role in ferroptosis and inflammation. Molecular docking studies further confirm the direct binding of BCA to both GPX4 and STAT3.

Conclusions: These results establish BCA as a promising natural compound for UC treatment, offering a novel therapeutic strategy by specifically targeting ferroptosis and its associated molecular pathways, thereby addressing key gaps in current UC management and advancing potential clinical applications.