Bruceine D induces ferroptosis in colorectal cancer by inhibiting STAT3 activity

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Background Colorectal cancer (CRC) is a globally prevalent gastrointestinal malignancy with rising incidence, and therapeutic resistance remains a major clinical challenge. Bruceine D (BD), a bioactive natural quassinoid from Brucea javanica , exerts anticancer effects in multiple tumors, but its role and mechanism in CRC remain largely unclear. This study aimed to investigate the antitumor activity of BD in CRC and explore its underlying molecular mechanism. Methods Core therapeutic targets of BD were predicted via integrated network pharmacology, molecular docking and 100 ns molecular dynamics simulations based on public datasets. The predicted mechanism was validated by in vitro cellular functional assays (CETSA, DARTS) and in vivo nude mouse xenograft models. Results BD dose-dependently inhibited proliferation and migration, and induced ferroptosis in RKO and HCT116 cells, characterized by downregulated GPX4 and xCT, reduced intracellular GSH, and elevated ROS and MDA levels. BD bound to STAT3 and suppressed its phosphorylation; STAT3 agonist ML115 significantly reversed BD-induced ferroptosis. In vivo , BD markedly attenuated tumor growth with favorable biosafety. Conclusions BD exerts antitumor effects in CRC by targeting STAT3 and promoting ferroptosis, supporting its potential as a novel therapeutic candidate for CRC treatment. Of note, core computational analyses in this study are in silico predictions, and the relevant mechanisms require further systematic validation.