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<p>Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment.</p>

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SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

  • 期刊论文

  • 发表日期：

    2025年10月27日

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  • Yijie Tao,
  • Shulei Yin,
  • Kai Wei,
  • Liyuan Zhao,
  • Yani Cui,
  • Chunzhen Li,
  • Yunyang Wu,
  • Panpan Hu,
  • Shenhui Yin,
  • Likun Cui,
  • Yunyan Zhang,
  • Yixian He,
  • Shu Yu,
  • Jie Chen,
  • Shaoteng Lu,
  • Guifang Qiu,
  • Mengqi Song,
  • Siqi Yang,
  • Qianshan Hou,
  • Yiquan Xue,
  • Chen Qian,
  • Sheng Xu,
  • Yizhi Yu,
  • Zui Zou

摘要

Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment.