IGF2BP3 enhances ferroptosis resistance in colon cancer by stabilizing SLC7A11 and is regulated by miR-98-5p.

PURPOSE: Colon cancer remains a global health challenge with rising mortality, necessitating novel therapeutic strategies. IGF2BP3, an oncogenic RNA-binding protein, is implicated in colon cancer progression, while its role in ferroptosis regulation remains unclear. This study investigates IGF2BP3's role in ferroptosis regulation and its interplay with miR-98-5p in colon cancer, aiming to identify therapeutic targets for enhancing ferroptosis sensitivity. METHODS: Bioinformatics analyses (TCGA, UALCAN, GEPIA) assessed IGF2BP3 expression and prognostic relevance in colon cancer. The expression of IGF2BP3 in clinical samples were analyzed via immunohistochemistry (IHC) and Western blotting. IGF2BP3-knockdown (KD) cell lines (HCT116/DLD-1) were generated using lentiviral shRNA. Ferroptosis sensitivity was evaluated via CCK-8 assays, MDA/ROS quantification, and rescue experiments with ferrostatin-1. Transcriptomic sequencing, RNA immunoprecipitation (RIP), and RNA stability assays identified IGF2BP3-regulated targets. Dual-luciferase reporter assays validated miR-98-5p-IGF2BP3 interactions. Xenograft models assessed in vivo tumor growth. RESULTS: IGF2BP3 was significantly upregulated in colon cancer tissues and correlated with advanced T-stage, higher clinical stage, and poor survival (p<0.05). Knockdown of IGF2BP3 enhanced erastin-induced ferroptosis sensitivity, marked by elevated MDA and ROS levels, reversible by ferrostatin-1. Mechanistically, IGF2BP3 stabilized SLC7A11 mRNA via direct binding and SLC7A11 overexpression rescued ferroptosis resistance in IGF2BP3-KD cells. miR-98-5p directly targeted IGF2BP3's 3'-UTR, suppressing its expression and enhancing ferroptosis sensitivity. In vivo, IGF2BP3-KD suppressed tumor growth and reduced Ki67/SLC7A11 expression. CONCLUSION: IGF2BP3 drives ferroptosis resistance in colon cancer by stabilizing SLC7A11 mRNA, while miR-98-5p antagonizes this pathway via IGF2BP3 downregulation. Targeting the miR-98-5p/IGF2BP3/SLC7A11 axis offers a promising therapeutic strategy to enhance ferroptosis sensitivity and improve colon cancer outcomes.