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<p>Genetic heterogeneity contributes to the variable therapeutic responses in cancers. Frequent <i>SPOP</i> mutations and recurrent <i>CHD1</i> deletions define distinct molecular subtypes of prostate cancer (PCa) with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify <i>SPOP</i> mutations and <i>CHD1</i> deletion as key genetic determinants of ferroptosis susceptibility in PCa. Using genetically engineered human and murine models, we show that <i>SPOP</i> mutations enhance, whereas <i>CHD1</i> deletion impairs, the efficacy of ferroptosis inducers targeting GPX4. Mechanistically, SPOP and CHD1 exert opposing effects on ferroptosis by antagonistically regulating the MYC–ACSL4 axis. Furthermore, we demonstrate that targeting cholesterol metabolism with cholesterol-lowering agents restores ACSL4 expression and re-sensitizes <i>SPOP/CHD1</i> co-deficient tumors to ferroptosis-inducing therapy. Our findings establish SPOP/CHD1 as upstream genetic regulators of ferroptosis and provide biomarker-driven combinatorial strategies to enhance ferroptosis-based therapy in men with advanced PCa.</p>

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Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Feiyu Chen,
  • Qidong Li,
  • Qianlin Gu,
  • Javier Leo,
  • Xin Liang,
  • Naayaa Mehta,
  • Estefania Labanca,
  • Peter Shepherd,
  • Iqbal Mahmud,
  • Yin Wang,
  • Francisco R. Saenz,
  • Maya M. Phillips,
  • Wei Shi,
  • Chenling Meng,
  • Jie Zhang,
  • Daniel E. Frigo,
  • Yue Lu,
  • Boyi Gan,
  • Di Zhao

摘要

Genetic heterogeneity contributes to the variable therapeutic responses in cancers. Frequent SPOP mutations and recurrent CHD1 deletions define distinct molecular subtypes of prostate cancer (PCa) with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify SPOP mutations and CHD1 deletion as key genetic determinants of ferroptosis susceptibility in PCa. Using genetically engineered human and murine models, we show that SPOP mutations enhance, whereas CHD1 deletion impairs, the efficacy of ferroptosis inducers targeting GPX4. Mechanistically, SPOP and CHD1 exert opposing effects on ferroptosis by antagonistically regulating the MYC–ACSL4 axis. Furthermore, we demonstrate that targeting cholesterol metabolism with cholesterol-lowering agents restores ACSL4 expression and re-sensitizes SPOP/CHD1 co-deficient tumors to ferroptosis-inducing therapy. Our findings establish SPOP/CHD1 as upstream genetic regulators of ferroptosis and provide biomarker-driven combinatorial strategies to enhance ferroptosis-based therapy in men with advanced PCa.