2. Academic Validation
  3. GPX4-dependent ferroptosis sensitivity is a fitness trade-off for cell enlargement

GPX4-dependent ferroptosis sensitivity is a fitness trade-off for cell enlargement

  • iScience. 2025 Apr 9;28(5):112363. doi: 10.1016/j.isci.2025.112363.
Kuan Yoow Chan 1 2,  Yini Yu 1,  Yidi Kong 1,  Ling Cheng 1,  Renzhi Yao 1,  Phoebe Sha Yin Chair 1,  Ping Wang 1,  Rong Wang 3,  Wan-Yang Sun 3,  Rong-Rong He 3,  Junxia Min 4,  Fudi Wang 5,  Mikael Björklund 1 2
Affiliations

Affiliations

  • 1 Centre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, 718 East Haizhou Road, Haining 314400, China.
  • 2 Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9JZ, UK.
  • 3 Guangdong Engineering Research Center of Traditional Chinese Medicine & Disease Susceptibility/Guangzhou Key Laboratory of Traditional Chinese Medicine & Disease Susceptibility/Guangdong-Hong Kong-Macao Universities Joint Laboratory for the Internationalization of Traditional Chinese Medicine/International Cooperative Laboratory of TCM Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China.
  • 4 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China.
PMID: 40330887 DOI: 10.1016/j.isci.2025.112363
Abstract

Despite wide variation, each cell type has an optimal size. Maintaining optimal size is essential for cellular fitness and function but the biological basis for this remains elusive. Here, we performed fitness analysis involving genome-wide CRISPR-Cas9 knockout data from tens of human cell lines and identified that cell size influences the essentiality of genes related to mitochondria and membrane repair. These genes also included Glutathione Peroxidase 4 (GPX4), which safeguards membranes from oxidative damage and prevents ferroptosis-iron-dependent death. Growth beyond normal size, with or without cell-cycle arrest, increased lipid peroxidation, resulting in a ferroptosis-sensitive state. Proteomic analysis revealed cell-cycle-independent superscaling of endoplasmic reticulum, accumulation of iron, and lipidome remodeling. Even slight increases from normal cell size sensitized proliferating cells to Ferroptosis as evidenced by deep-learning-based single-cell analysis. Thus, lipid peroxidation may be a fitness trade-off that constrains cell enlargement and contributes to the establishment of an optimal cell size.

Keywords

Biochemistry; Cell biology; Molecular biology.

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