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<p>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 <i>STX17-DT</i> as a driver of therapy resistance in RCC. The expression of <i>STX17-DT</i> was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of <i>STX17-DT</i> contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, <i>STX17-DT</i> modulated the stability of <i>IFI6</i> mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial reactive oxygen species (ROS) and attenuated ferroptosis. Meanwhile, <i>STX17-DT</i> was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to other cells. Compared with axitinib monotherapy, combined treatment of axitinib and <i>STX17-DT-</i>targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that <i>STX17-DT</i> may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月23日

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  • Yihui Pan,
  • Shuang Liu,
  • Guannan Shu,
  • Minyu Chen,
  • Liangmin Fu,
  • Cheng Chen,
  • Yimeng Chen,
  • Qianfeng Zhuang,
  • Dong Xue,
  • Xiaozhou He

摘要

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.