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<p>Ferroptosis is closely linked with various pathophysiological processes, including aging, neurodegeneration, ischemia-reperfusion injury, viral infection and, notably, cancer progression; however, its post-translational regulatory mechanisms remain incompletely understood. Here we revealed a crucial role of S-palmitoylation in regulating ferroptosis through glutathione peroxidase 4 (GPX4), a pivotal enzyme that mitigates lipid peroxidation. We identified that zinc finger DHHC-domain containing protein 8 (zDHHC8), an S-acyltransferase that is highly expressed in multiple tumors, palmitoylates GPX4 at Cys75. Through small-molecule drug screening, we identified PF-670462, a zDHHC8-specific inhibitor that promotes the degradation of zDHHC8, consequently attenuating GPX4 palmitoylation and enhancing ferroptosis sensitivity. PF-670462 inhibition of zDHHC8 facilitates the CD8<sup>+</sup> cytotoxic T cell-induced ferroptosis of tumor cells, thereby improving the efficacy of cancer immunotherapy in a B16-F10 xenograft model. Our findings reveal the prominent role of the zDHHC8–GPX4 axis in regulating ferroptosis and highlight the potential application of zDHHC8 inhibitors in anticancer therapy.</p>

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Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity

  • 期刊论文

  • 发表日期：

    2025年3月19日

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  • Liang Zhou,
  • Guangyu Lian,
  • Tao Zhou,
  • Zhe Cai,
  • Shuai Yang,
  • Weining Li,
  • Lilin Cheng,
  • Ying Ye,
  • Mingfeng He,
  • Jianru Lu,
  • Qifeng Deng,
  • Bihui Huang,
  • Xiaoqian Zhou,
  • Desheng Lu,
  • Feng Zhi,
  • Jun Cui

摘要

Ferroptosis is closely linked with various pathophysiological processes, including aging, neurodegeneration, ischemia-reperfusion injury, viral infection and, notably, cancer progression; however, its post-translational regulatory mechanisms remain incompletely understood. Here we revealed a crucial role of S-palmitoylation in regulating ferroptosis through glutathione peroxidase 4 (GPX4), a pivotal enzyme that mitigates lipid peroxidation. We identified that zinc finger DHHC-domain containing protein 8 (zDHHC8), an S-acyltransferase that is highly expressed in multiple tumors, palmitoylates GPX4 at Cys75. Through small-molecule drug screening, we identified PF-670462, a zDHHC8-specific inhibitor that promotes the degradation of zDHHC8, consequently attenuating GPX4 palmitoylation and enhancing ferroptosis sensitivity. PF-670462 inhibition of zDHHC8 facilitates the CD8+ cytotoxic T cell-induced ferroptosis of tumor cells, thereby improving the efficacy of cancer immunotherapy in a B16-F10 xenograft model. Our findings reveal the prominent role of the zDHHC8–GPX4 axis in regulating ferroptosis and highlight the potential application of zDHHC8 inhibitors in anticancer therapy.