SLC38A5 drives colorectal cancer ferroptosis resistance through the Hippo-YAP/Nrf2 axis

Colorectal cancer (CRC), a malignancy characterized by high aggressiveness, metastatic propensity, frequent recurrence, and poor prognosis, underscores the critical need for identifying biomarkers to guide targeted therapeutic strategies. Solute carrier family 38 member 5 (SLC38A5) emerges as a promising target due to its pharmacological tractability and role in cancer progression. In this study, we demonstrate that SLC38A5 promoted CRC progression through both bioinformatic analysis and experimental validation. Knockdown of SLC38A5 significantly suppressed cell viability, colony formation, and migratory ability in DLD1 and HCT116 cells. Notably, SLC38A5 depletion sensitized CRC cells to RSL3-induced ferroptosis. Mechanistically, SLC38A5 inhibition down-regulated antioxidant-related genes Nrf2 and Heme Oxygenase 1 (HO-1) and key ferroptosis regulators GPX4 and SLC7A11, while modulating Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Stearoyl-CoA Desaturase 1 (SCD1) expression. Additionally, SLC38A5 knockdown impaired nuclear translocation of YAP, the core transcriptional co-activator in the Hippo signaling pathway. ‌Chromatin immunoprecipitation (ChIP) analysis demonstrated the binding of YAP to Nrf2. Our findings reveal a novel mechanism wherein SLC38A5 confers ferroptosis resistance in CRC via YAP nuclear translocation within the Hippo signaling pathway. Collectively, this study highlights SLC38A5 as a potential therapeutic target to enhance ferroptosis-based cancer therapy, offering new strategies to improve CRC treatment outcomes.