2. Academic Validation
  3. Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis

Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis

  • Nat Commun. 2025 Jan 20;16(1):867. doi: 10.1038/s41467-025-56344-5.
Bin Huang # 1 2,  Hui Wang # 2 3,  Shuo Liu # 4,  Meng Hao # 2,  Dan Luo 2,  Yi Zhou 2 5,  Ying Huang 2 6,  Yong Nian 7,  Lei Zhang 1 2 3,  Bo Chu 8,  Chengqian Yin 9 10
Affiliations

Affiliations

  • 1 School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Peking University, Shenzhen, Guangdong, China.
  • 2 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
  • 3 Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong, China.
  • 4 Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  • 5 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 6 School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, China.
  • 7 College of Pharmacy, Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 8 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 9 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China. yincq@szbl.ac.cn.
  • 10 Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong, China. yincq@szbl.ac.cn.
  • # Contributed equally.
PMID: 39833225 DOI: 10.1038/s41467-025-56344-5
Abstract

S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of Ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of Ferroptosis, is reversibly palmitoylated on cysteine 66. The Acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability. ZDHHC20 depletion or inhibition of protein palmitoylation by 2-BP sensitizes Cancer cells to Ferroptosis. Moreover, we identify APT2 as the depalmitoylase of GPX4. Genetic silencing or pharmacological inhibition of APT2 with ML349 increases GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to Ferroptosis. Notably, disrupting GPX4 palmitoylation markedly potentiates Ferroptosis in xenografted and orthotopically implanted tumor models, and inhibits tumor metastasis through blood vessels. In the chemically induced colorectal Cancer model, knockout of APT2 significantly aggravates Cancer progression. Furthermore, pharmacologically modulating GPX4 palmitoylation impacts liver ischemia-reperfusion injury. Overall, our findings uncover the intricate network regulating GPX4 palmitoylation, highlighting its pivotal role in modulating Ferroptosis sensitivity.

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