otud3介导的SLC7A11稳定通过抑制透明细胞肾细胞癌中的铁下垂驱动舒尼替尼耐药

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-07-25 DOI:10.1016/j.canlet.2025.217942

Tian Xu , Huimin Liu , Neng Ling , Daiquan Chen , Jing Dai , Wenjing Chen , Yuxuan Li , Xirong Gao , Wei Zhai , Mao Ye , Yang Sun , Weihong Tan

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引用次数: 0

摘要

透明细胞肾细胞癌（Clear cell renal cell carcinoma, ccRCC）作为RCC的主要类型，晚期应用酪氨酸激酶抑制剂（tyrosine kinase inhibitor， TKI）治疗。虽然耐药是苏尼替尼等tki类药物的主要挑战，但其潜在机制尚不清楚。在这里，我们发现OTUD3在ccRCC中过表达，并促进肿瘤细胞对舒尼替尼的耐药性。OTUD3去泛素化胱氨酸/谷氨酸转运体SLC7A11，保护其免受蛋白酶体降解，促进胱氨酸转运进入细胞，降低细胞内ROS水平，从而抑制舒尼替尼诱导的铁凋亡。我们的研究结果表明，靶向OTUD3可能是一种潜在的策略，可以增强铁下垂，提高舒尼替尼在ccRCC中的治疗效果。

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OTUD3-mediated stabilization of SLC7A11 drives sunitinib resistance by suppressing ferroptosis in clear cell renal cell carcinoma

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.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.