Curcumin prevents ferroptosis and shields against cerebral ischemia-reperfusion injury by modulating GPX4 H3K18ac via KLF2

Abstract

Abstract Cerebral ischemia-reperfusion injury (CIRI) involves complex pathological mechanisms, including ferroptosis. Curcumin exhibits neuroprotective properties, but its role in modulating ferroptosis during CIRI remains incompletely understood. This research explored how curcumin protects against ferroptosis in CIRI and the molecular mechanisms involved. In vivo, male MCAO rats were divided into Sham, MCAO, and curcumin low/medium/high-dose groups. Infarct volume, neurological deficit scores, and ferroptosis markers (MDA, Fe2+, GSH, GPX4, FTH1, TfR1) were detected. In vitro, OGD/R-stimulated BV2 cells were administered with curcumin or Ferrostatin-1. GPX4 knockdown, KLF2, and KAT2A overexpression or knockdown were performed. ChIP, CCK-8, and western blotting were applied to identify H3K18ac modification, cell viability, and protein expression, respectively. In MCAO rats, curcumin administration led to a reduction in infarct size, better neurological outcomes, and a decrease in ferroptosis. In vitro, curcumin inhibited OGD/R-stimulated ferroptosis and enhanced H3K18 acetylation at the GPX4 promoter. Mechanistically, curcumin upregulated the transcription factor KLF2, which transcriptionally activated the histone acetyltransferase KAT2A. KAT2A mediated H3K18ac modification at the GPX4 promoter, leading to GPX4 upregulation and ferroptosis suppression. KLF2 knockdown abolished the protective effects of curcumin. In conclusion, Curcumin inhibited ferroptosis in CIRI by activating the KLF2/KAT2A/GPX4 signaling axis, highlighting a novel epigenetic mechanism and potential therapeutic strategy for ischemic stroke. HIGHLIGHTS Curcumin prevented ferroptosis in MCAO rats Curcumin enhanced GPX4 H3K18ac modification and inhibited ferroptosis KAT2A mediated GPX4 H3K18ac modification and suppressed BV2 cells ferroptosis under OGD/R conditions KLF2 transcriptionally activated KAT2A and inhibited OGD/R-stimulated BV2 cells ferroptosis By activating the KLF2/KAT2A/GPX4 axis, curcumin prevented ferroptosis in BV2 cells subjected to OGD/R.