SCARB1 links cholesterol metabolism-mediated ferroptosis inhibition to radioresistance in tumor cells

Ferroptosis is an iron-dependent form of cell death triggered by the excessive accumulation of lipid peroxides. Understanding the regulatory mechanisms of ferroptosis and developing strategies to target this process hold significant clinical applications in tumor therapy. Our study aims to search for novel candidate genes involved in the regulation of ferroptosis and to investigate their mechanism of action in ferroptosis and tumor therapy. We employed a CRISPR-Cas9 library to perform a genome-wide screen under ferroptosis inducer treatment conditions, revealing Scavenger Receptor Class B Member 1(SCARB1) as a novel candidate gene involved in ferroptosis regulation. Subsequently, lipidomic analyses, metabolic interventions, and relevant cellular experimental analyses were performed to elucidate the role of SCARB1 in ferroptosis, lipid peroxidation, and tumor therapy. Our study confirmed that SCARB1 significantly inhibits ferroptosis and lipid peroxidation induced by ferroptosis inducers. Mechanistically, SCARB1 inhibits ferroptosis through the regulation of cholesterol metabolism, and the upregulation of CoQ10 level is demonstrated to mediate the suppression of ferroptosis by SCARB1 after lipidomic analysis and metabolic intervention. Interestingly, SCARB1 exerts a tumor suppressive effect regarding tumor growth, migration and invasion, which is possibly independent of ferroptosis regulation. However, SCARB1 promotes radioresistance through the upregulation of cholesterol metabolism and inhibition of ferroptosis, while the combination of ferroptosis inducers can overcome radioresistance in tumor cells with high SCARB1 expression. This study establishes a theoretical foundation for the regulation of ferroptosis by SCARB1 and highlights the potential of targeting lipid metabolism to overcome radioresistance in cancer therapy. The identification of SCARB1 as a key player in ferroptosis and its dual role in tumor suppression and radioresistance provides new avenues for therapeutic intervention in cancer treatment.