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

Liang Zhou ¹, Guangyu Lian ¹, Tao Zhou ¹

¹MOE 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.
²Guangzhou Institute of Pediatrics, Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
³Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁴Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁵Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
⁶Department of Gastrointestinal Surgery, The First People's Hospital of Gui Yang, Gui Yang, China.
⁷Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China.
⁸Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, China.
⁹MOE 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.

⁰MOE 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.

Nature Cancer +

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March 20, 2025

View abstract on PubMed

Summary

S-palmitoylation regulates ferroptosis via glutathione peroxidase 4 (GPX4). Inhibiting zinc finger DHHC-domain containing protein 8 (zDHHC8) enhances ferroptosis and cancer immunotherapy efficacy.

Area Of Science

Biochemistry
Molecular Biology
Oncology

Background

Ferroptosis, a regulated cell death, is implicated in aging, neurodegeneration, and cancer.
The post-translational regulation of ferroptosis, particularly involving glutathione peroxidase 4 (GPX4), is not fully understood.

Purpose Of The Study

To elucidate the role of S-palmitoylation in ferroptosis regulation.
To investigate the specific mechanisms involving GPX4 and its regulatory enzymes in cancer.

Main Methods

Identified zDHHC8 as an S-acyltransferase that palmitoylates GPX4 at Cys75.
Conducted small-molecule drug screening to identify zDHHC8 inhibitors.
Utilized a B16-F10 xenograft model to assess therapeutic efficacy.

Main Results

zDHHC8 was found to palmitoylate GPX4, a key enzyme in mitigating lipid peroxidation.
PF-670462, a zDHHC8 inhibitor, was identified, leading to decreased GPX4 palmitoylation and increased ferroptosis sensitivity.
Inhibition of zDHHC8 enhanced CD8+ cytotoxic T cell-mediated ferroptosis and improved cancer immunotherapy outcomes.

Conclusions

The zDHHC8-GPX4 axis is a critical regulator of ferroptosis.
Targeting zDHHC8 with inhibitors like PF-670462 shows potential for enhancing cancer therapy and immunotherapy.