Triggering SORL1 Expression Restricts ccRCC Progression by Inducing Ubiquitination‐Mediated c‐Myc Degradation

Abstract

ABSTRACT Clear cell renal cell carcinoma (ccRCC) represents one of the most prevalent malignancies worldwide, characterized by high incidence and mortality rates. It is characterized by mitochondrial dysfunction with enhanced Warburg effect. In this study, we identify the sortilin‐related receptor 1 (SORL1) as a regulator of ccRCC progression and a potential molecular target for oxidative phosphorylation inhibition. The present evidence demonstrates that SORL1 promotes the ubiquitin‐mediated degradation of C‐MYC via TRIM22, which is associated with the downregulation of ACO2 and IDH2 and a consequent suppression of oxidative phosphorylation capacity. Molecular investigations further indicated that Cefoperazone could bind to SORL1 and increase its protein level, exerting the SORL1‐triggering function. Targeting delivery Cefoperazone exhibits unexpected anti‐tumor performances in ccRCC. Collectively, our findings establish SORL1 as a tumor suppressor in ccRCC and highlight its potential as a therapeutic target in advancing ccRCC clinical treatment strategies.