Ferroptosis, an iron-dependent regulated cell death marked by lipid peroxidation accumulation, is influenced by amino acid, lipid, redox, and iron metabolisms. This study reveals that O-GlcNAcylation, a glucose flux sensor, orchestrates ferritinophagy and mitophagy to activate ferroptosis. Following ferroptosis stimuli (e.g., RSL3), O-GlcNAcylation exhibits a biphasic change. Inhibition of O-GlcNAcylation enhances ferritinophagy, increasing labile iron in mitochondria, and promotes mitophagy, further increasing labile iron and ferroptosis sensitivity. De-O-GlcNAcylation of ferritin heavy chain S179 boosts its interaction with NCOA4 (ferritinophagy receptor), leading to labile iron accumulation and ferroptosis. This research establishes a novel link between dynamic O-GlcNAcylation, iron metabolism, and ferroptosis decision-making, suggesting potential therapeutic avenues.

Fan Yu, Qianping Zhang, Hanyu Liu, Jinming Liu, Song Yang, Xiaofan Luo, Wei Liu, Hao Zheng, Qiqi Liu, Yunxi Cui, Guo Chen, Yanjun Li, Xinglu Huang, Xiyun Yan, Jun Zhou, Quan Chen