Scholarlink

<p>Targeted therapy resistance has become a major challenge for hepatocellular carcinoma (HCC) treatment. Triggering ferroptosis emerges as a promising strategy to overcome therapeutic resistance. Here, we have identified ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, contributing to HCC resistance by inhibiting sorafenib-induced ferroptosis. Nuclear receptor coactivator 4 (NCOA4), a crucial regulator of ferroptosis, turned out to be a novel downstream effector of USP18 and is posttranslationally suppressed. Such regulation is based on the USP18-mediated deISGylation and degradation process. Additionally, we have demonstrated that sorafenib promotes USP18 accumulation in HCC via the STING/IRF3/ISG15 axis. Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月13日

查看全文
  • Shengtao Ye,
  • Junxin Chen,
  • Ying Zheng,
  • Mengmeng He,
  • Yanqiu Zhang,
  • Yang Cheng,
  • Yingrong Leng,
  • Enyi Wu,
  • Lingyi Kong,
  • Hao Zhang

摘要

Targeted therapy resistance has become a major challenge for hepatocellular carcinoma (HCC) treatment. Triggering ferroptosis emerges as a promising strategy to overcome therapeutic resistance. Here, we have identified ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, contributing to HCC resistance by inhibiting sorafenib-induced ferroptosis. Nuclear receptor coactivator 4 (NCOA4), a crucial regulator of ferroptosis, turned out to be a novel downstream effector of USP18 and is posttranslationally suppressed. Such regulation is based on the USP18-mediated deISGylation and degradation process. Additionally, we have demonstrated that sorafenib promotes USP18 accumulation in HCC via the STING/IRF3/ISG15 axis. Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.