2. Academic Validation
  3. The protective role of GPX4 in naïve ESCs is highlighted by induced ferroptosis resistance through GPX4 expression

The protective role of GPX4 in naïve ESCs is highlighted by induced ferroptosis resistance through GPX4 expression

  • Redox Biol. 2025 Apr:81:103539. doi: 10.1016/j.redox.2025.103539.
Seokwoo Park 1,  Mihn Jeong Park 2,  Eun-Ji Kwon 2,  Ji-Young Oh 2,  Yeon-Joon Chu 2,  Han Sun Kim 3,  Sunghyouk Park 3,  Tae Ha Kim 2,  Sung Won Kwon 2,  Yon Su Kim 4,  Hyuk-Jin Cha 5
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
  • 2 College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 3 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 4 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 5 College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address: hjcha93@snu.ac.kr.
PMID: 40010136 DOI: 10.1016/j.redox.2025.103539
Abstract

Ferroptosis, a form of oxidative cell death mediated by lipid peroxidation, is strictly regulated by Glutathione Peroxidase 4 (GPX4). Knockout of Gpx4 results in embryonic lethality, highlighting its essential role in development. In vitro, mouse embryonic stem cells (mESCs), which represent the naïve pluripotent state, require β-mercaptoethanol (bME) to prevent cell death, unlike human embryonic stem cells, which represent the primed state. We hypothesized that naïve pluripotency is linked to a heightened susceptibility to Ferroptosis due to unique metabolic demands and redox imbalances. In this study, we found that bME deprivation induces Ferroptosis in naïve ESCs, as evidenced by lipid peroxidation; Ferroptosis, however, is less evident in primed ESCs. Mechanistic analyses revealed that active Oxidative Phosphorylation (OXPHOS) in naïve ESCs increased mitochondrial Reactive Oxygen Species. Consistent with the upregulation of Gpx4 transcripts and OXPHOS-associated gene sets seen in the inner cell mass of blastocysts, stable GPX4 expression conferred resistance to Ferroptosis induced by bME withdrawal. These results suggest that the unique redox and metabolic landscape of naïve ESCs highlits a potential requirement for GPX4 in maintaining naïve pluripotency, providing insights into early developmental processes and vulnerabilities.

Keywords

Ferroptosis; Glutathione peroxidase 4 (GPX4); Naïve pluripotency; Primed pluripotency.

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