Matrine induces ferroptosis and suppresses colorectal cancer through targeting the STAT3/SLC7A11 pathway

Matrine, a natural alkaloid with recognized anti-cancer potential, has been reported to induce cancer cell death. However, the mechanism remains incompletely defined. In this study, we investigated the pharmacological effect of matrine on colorectal cancer (CRC) using both in vivo tumor‑bearing mouse models and in vitro cell cultures. Our results demonstrated that matrine effectively suppressed colorectal cancer progression in mice, accompanied by an increased area of tumor necrosis and enhanced infiltration of anti-tumor immune cells, including CD4⁺ and CD8⁺ T-cells. Importantly, matrine treatment increased 4-hydroxynonenal (4-HNE) staining, a marker of ferroptosis, in tumor tissues. In vitro, matrine induced dose-dependent cell death in CRC cells, which was rescued by the ferroptosis inhibitors ferrostatin-1 (Fer-1) or liproxstatin-1 (Lip-1). Matrine promoted lipid peroxidation, as evidenced by increased BODIPY⁺ cells and elevated malondialdehyde (MDA) levels, alongside reduced glutathione (GSH). Mechanistically, matrine downregulated SLC7A11 and upregulated p53 expression. Further analysis revealed that matrine inhibited the phosphorylation of STAT3, a common upstream regulator of both SLC7A11 and p53. Rescue experiments showed that the antitumor effect of matrine depended on STAT3 inhibition, not on p53. Molecular docking showed that matrine could bind to the phosphotyrosine‑binding pocket of STAT3. Taken together, we revealed that matrine showed a significant inhibitory effect on CRC. The present findings identify a previously unrecognized mechanism through which matrine controls tumor cell fate by modulating ferroptosis, providing mechanistic insight into STAT3/SLC7A11-dependent regulation.