MEF2C protects against neuronal ferroptosis post-intracerebral hemorrhage through the upregulation of FGF21

Ferroptosis plays a critical role in secondary brain injury following intracerebral hemorrhage (ICH). However, the regulatory mechanisms governing ferroptosis after ICH remain unexplored. By transcriptome sequencing of brain tissues from ICH patients and mouse models, we identified myocyte enhancer factor 2C (MEF2C) as a key ferroptosis-related gene. MEF2C was downregulated in human and mouse ICH brains and mainly localized to neurons. Neuron-specific MEF2C overexpression suppressed ferroptosis and improved neurological outcomes after ICH in mice. We further overexpressed and knocked out MEF2C in the mouse neuronal cell line HT22 and conducted in vitro experiments using hemoglobin (Hb) and ferroptosis inducers (RSL3 and erastin). Our findings indicated that MEF2C inhibited reactive oxygen species (ROS) accumulation, lipid peroxidation, and Fe 2+ overload, thereby inhibiting ferroptosis. Subsequent transcriptomic analysis identified fibroblast growth factor 21 (FGF21), a protein previously reported to regulate ferroptosis, as a downstream gene of MEF2C. Dual-luciferase and chromatin immunoprecipitation assays confirmed that MEF2C directly activates Fgf21 transcription. Finally, the in vitro model of ICH demonstrated that FGF21 modulates oxidant stress and Fe 2+ accumulation and that FGF21 knockdown abrogated MEF2C-reduced oxidative stress and Fe 2+ accumulation, indicating that FGF21 is required for MEF2C-mediated anti-ferroptosis. Taken together, MEF2C protects against ICH-induced ferroptosis by transcriptionally regulating FGF21. Our work provides new insights and potential therapeutic targets for the treatment of ICH.