STRIP2 Stabilizes LCN2 to Suppress Ferroptosis and Drives Colorectal Cancer Malignancy

Colorectal cancer (CRC) presents a significant global health challenge with high incidence rates, mortality, and poor five-year survival rates, particularly in advanced cases, despite the availability of existing treatments. This study investigates the role of Striatin-interacting protein 2 (STRIP2) in CRC progression and the underlying mechanisms. To evaluate the impact of STRIP2 on CRC, in vitro experiments were conducted to assess cell proliferation, migration, invasion, and apoptosis in CRC cell lines. Furthermore, in vivo studies were performed utilizing nude mouse models. Transcriptomic analysis, Western blotting, co-immunoprecipitation assays, and ferroptosis validation were employed to elucidate the role of STRIP2 in CRC. The findings indicate that STRIP2 is overexpressed in CRC and drives malignant behaviors in both in vitro and in vivo settings. Overexpressing STRIP2 (oe-STRIP2) suppresses ferroptosis, leading to increased cell proliferation and reduced oxidative stress, whereas silencing STRIP2 (si-STRIP2) has the opposite effect. Mechanistically, STRIP2 stabilizes LCN2, an effector downstream of IL-17, by preventing its K48-linked ubiquitination and subsequent degradation. This stabilization sequentially inhibits the ferroptosis defense mechanism and enhances the anti-ferroptosis capacity of CRC cells, thereby promoting cell survival and facilitating malignant progression in CRC. This study establishes a novel, unrecognized post-translational regulatory axis: STRIP2–LCN2–ferroptosis that drives CRC progression and chemoresistance.