Epiandrosterone attenuates neuronal ferroptosis after subarachnoid hemorrhage by OGT-mediated FTH O-GlcNAcylation to suppress NCOA4-dependent ferritinophagy.

Ferritin heavy chain (FTH) serves as the central iron-storage protein in neurons, yet the regulatory mechanisms governing its stability after subarachnoid hemorrhage (SAH) remain poorly understood. We observed a striking paradox: although Fth mRNA levels were upregulated following SAH, FTH protein expression declined precipitously, suggesting the involvement of active post-transcriptional regulation. Here we demonstrate that O-GlcNAc transferase (OGT) protects FTH from autophagic degradation by catalyzing O-GlcNAcylation at Serine 7 (S7), a modification that physically prevents the autophagy receptor NCOA4 from binding to FTH. SAH suppresses OGT expression, removes this protective S7 glycosylation, and enables NCOA4-mediated ferritinophagy, leading to iron overload, lipid peroxidation, and neuronal ferroptosis. To identify therapeutic interventions targeting this mechanism, we performed metabolomic screening of cerebrospinal fluid from SAH patients and identified the endogenous steroid epiandrosterone (EpiA) as an allosteric OGT agonist. EpiA binds to OGT, enhances its catalytic efficiency, and restores FTH S7 O-GlcNAcylation. In a rat SAH model, EpiA treatment efficiently blocked ferritinophagy, attenuated oxidative injury, preserved neuronal viability, and improved functional outcomes. These findings uncover a post-translational mechanism that governs ferritin stability and ferroptosis susceptibility, and they validate EpiA as a lead compound that engages this pathway to confer neuroprotection after SAH.