Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.

ABSTRACT: FOXO transcription factors act downstream of PI3K signaling, and FOXO transcriptional activity is inhibited through nuclear exclusion by PKB/AKT-mediated phosphorylation. Many studies have shown FOXO to contribute to organismal homeostasis by mitigating (extra)cellular stress to prevent cell death (reviewed in [1]). Here we show that FOXO3 activation protects cells from ferroptosis, an iron-dependent form of non-apoptotic cell death. In untransformed hTERT-RPE-1 cells, FOXO3 activation reduces ferroptosis in a multilayered manner. First, FOXO3 mediates protection from ferroptosis in part through a p27-induced G1 cell cycle arrest. Second, FOXO3 activation reduces cellular H₂O₂ levels, thereby limiting substrate availability for the Fenton reaction, which fuels hydroxy

SUBMITTER: Huang H 

PROVIDER: S-EPMC12533257 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature