Biochanin A promotes KLF6 stabilization to induce ferroptosis and suppress colorectal cancer progression.

RATIONALE: Colorectal cancer (CRC) is a prevalent malignancy of the digestive system, originating from the epithelial cells in the colon or rectum and commonly arising from adenomatous polyps. Over time, CRC may progress to advanced disease and metastasis, resulting in limited therapeutic options and poor clinical outcomes. Biochanin A (BCA), a naturally occurring isoflavonoid, has been shown to possess a range of biological activities, including antioxidant and anti-inflammatory effects. However, the precise effects of BCA on colorectal cancer and the underlying mechanisms remain poorly understood. METHODS: The malignant characteristics of the tumor were validated through scratch assays, CCK-8, and other experimental techniques. Ferroptosis-associated changes were evaluated using C11-BODIPY, transmission electron microscopy (TEM), reactive oxygen species detection, and other relevant assays. The specific mechanism of BCA action was explored using Pull-down and co-immunoprecipitation (Co-IP) assays. RESULTS: This research demonstrated that BCA significantly inhibits colorectal cancer cell proliferation and migration and enhances the inhibitory effects of chemotherapeutic treatment on colorectal cancer cells. More specifically, BCA appears to enhance USP22-KLF6 interaction by binding to KLF6, thereby promoting KLF6 protein stabilization and regulating the KLF6/ACSL4/LPCAT3 axis, which is associated with increased ferroptotic vulnerability in colorectal cancer cells. CONCLUSIONS: BCA suppresses colorectal cancer progression by modulating the USP22-KLF6-ACSL4/LPCAT3 axis, which is associated with ferroptosis-related responses.