Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance.

5-Fluorouracil (5-Fu) remains essential in colorectal cancer (CRC) treatment, but monotherapy causes severe toxicity and faces chemoresistance. Combination regimens are encouraged to improve efficacy and safety. Natural compounds like Baicalin show anti-tumor potential in other gastrointestinal cancers, yet their role in CRC, particularly in overcoming 5-Fu resistance, is underexplored. The combined effect of Baicalin and 5-Fu was evaluated through in vitro functional assays and an in vivo xenograft model. Mechanisms were investigated using Western blot, qPCR, and RNA-seq. Baicalin enhanced 5-Fu to inhibit CRC progression both in vitro and in vivo. Mechanistically, Baicalin enhanced 5-Fu cytotoxicity by activating the MLKL-dependent necroptosis pathway. This study proposes the Baicalin and 5-Fu combination as a novel and potent chemosensitizing strategy for CRC, especially in 5-Fu-resistant cases, and provides a mechanistic rationale for Baicalin as a chemotherapy-enhancing agent.