2. Academic Validation
  3. Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity

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

  • Nat Cancer. 2025 May;6(5):768-785. doi: 10.1038/s43018-025-00937-y.
Liang Zhou 1,  Guangyu Lian 1,  Tao Zhou 1,  Zhe Cai 2,  Shuai Yang 1,  Weining Li 1,  Lilin Cheng 1,  Ying Ye 3,  Mingfeng He 4,  Jianru Lu 1,  Qifeng Deng 1,  Bihui Huang 5,  Xiaoqian Zhou 6,  Desheng Lu 7,  Feng Zhi 8,  Jun Cui 9
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China.
  • 2 Guangzhou Institute of Pediatrics, Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 3 Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
  • 6 Department of Gastrointestinal Surgery, The First People's Hospital of Gui Yang, Gui Yang, China.
  • 7 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China.
  • 8 Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, China.
  • 9 MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China. cuij5@mail.sysu.edu.cn.
PMID: 40108413 DOI: 10.1038/s43018-025-00937-y
Abstract

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.

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