2. Academic Validation
  3. STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis

STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis

  • Cell Death Dis. 2025 Feb 23;16(1):125. doi: 10.1038/s41419-025-07456-9.
Yihui Pan # 1,  Shuang Liu # 2,  Guannan Shu # 3 4,  Minyu Chen # 5,  Liangmin Fu # 6 7,  Cheng Chen 8,  Yimeng Chen 8,  Qianfeng Zhuang 8,  Dong Xue 9,  Xiaozhou He 10
Affiliations

Affiliations

  • 1 Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China. panyihui0314@163.com.
  • 2 Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, China.
  • 3 Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 4 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 5 Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 7 Uro-Oncology Institute of Central South University, Changsha, Hunan, China.
  • 8 Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China.
  • 9 Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China. xuedongdx@163.com.
  • 10 Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China. Hxz911@sina.com.
  • # Contributed equally.
PMID: 39988631 DOI: 10.1038/s41419-025-07456-9
Abstract

Axitinib resistance remains a serious challenge in the treatment of advanced renal cell carcinoma (RCC), and the underlying mechanisms are not fully understood. Here, we constructed an in vivo axitinib-resistant RCC model and identified the long non-coding RNA STX17-DT as a driver of therapy resistance in RCC. The expression of STX17-DT was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of STX17-DT contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, STX17-DT modulated the stability of IFI6 mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial Reactive Oxygen Species (ROS) and attenuated Ferroptosis. Meanwhile, STX17-DT was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to Other cells. Compared with axitinib monotherapy, combined treatment of axitinib and STX17-DT-targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that STX17-DT may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.

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    99.94%, Tyrosine Kinase Inhibitor
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