Abstract

Y box binding protein 3 (YBX3) is an oncogene in clear cell renal cell carcinoma (ccRCC). This study aimed to investigate ubiquitin-specific proteases (USPs) that regulate YBX3 stability in ccRCC. USP18 was identified as a potent stabilizer of YBX3, and USP18 was depleted to assess its impact on the malignant behavior of ccRCC cells and on YBX3 ubiquitination. Subsequently, YBX3 was overexpressed in USP18-deficient cells to determine whether it could rescue the attenuated malignant phenotypes. A xenograft model and ccRCC organoids were also used to examine the effect of USP18 on ccRCC. USP18 knockdown caused reduced viability, arrested cell cycle, increased apoptosis, attenuated migration and invasion of ccRCC cells. Mechanistically, USP18 reduces ubiquitination and stabilizes YBX3 in ccRCC cells. In vivo , USP18 deficiency inhibits xenograft tumor growth by decreasing YBX3 expression and blocking the PI3K/AKT pathway. Our findings underscore the therapeutic potential of targeting the USP18-YBX3 axis in ccRCC treatment.