Xu Tian, Liu Huimin, Ling Neng, Chen Daiquan, Dai Jing, Chen Wenjing, Li Yuxuan, Gao Xirong, Zhai Wei, Ye Mao, Sun Yang, Tan Weihong
Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China.
Cancer Lett. 2025 Nov 1;632:217942. doi: 10.1016/j.canlet.2025.217942. Epub 2025 Jul 25.
Clear cell renal cell carcinoma (ccRCC), as the main type of RCC was treated with tyrosine kinase inhibitor (TKI) at the late stage. While drug resistance is the main challenge for TKIs like sunitinib, and the underline mechanisms remain unclear. Here, we found that OTUD3 is over-expressed in ccRCC and promotes sunitinib resistance in tumor cells. OTUD3 deubiquitinates the cystine/glutamate transporter SLC7A11 and protect it from proteasome degradation, which promotes cystine transport into cells and reduces intracellular ROS levels, thereby inhibiting sunitinib-induced ferroptosis. Our findings suggest that targeting OTUD3 could be a potential strategy to enhance ferroptosis and improve the therapeutic efficacy of sunitinib in ccRCC.
透明细胞肾细胞癌（ccRCC）作为肾细胞癌的主要类型，在晚期采用酪氨酸激酶抑制剂（TKI）进行治疗。然而，耐药性是舒尼替尼等TKI面临的主要挑战，其潜在机制仍不清楚。在此，我们发现OTUD3在ccRCC中过度表达，并促进肿瘤细胞对舒尼替尼的耐药性。OTUD3使胱氨酸/谷氨酸转运体SLC7A11去泛素化，并保护其免受蛋白酶体降解，从而促进胱氨酸转运进入细胞并降低细胞内ROS水平，进而抑制舒尼替尼诱导的铁死亡。我们的研究结果表明，靶向OTUD3可能是增强铁死亡并提高舒尼替尼在ccRCC中治疗效果的潜在策略。
