Abstract

Background Ischemic stroke (IS) is an acute cerebrovascular condition marked by high prevalence, high disability and high mortality rates. Previous studies have indicated that BTB and CNC homology 1 (BACH1) promotes ferroptosis in IS. However, the research on its specific molecular mechanism remains at an early stage. Methods To mimic the cell models of IS, SK-N-SH cells were induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Protein levels were tested by Western blot. CCK-8, TUNEL, flow cytometry, and Enzyme-linked Immunosorbent assay were employed to monitor viability, apoptosis, and inflammatory response. Additionally, Fe 2+ , malondialdehyde (MDA), glutathione (GSH) and reactive oxygen species (ROS) levels were detected using relevant kits. Methylated RNA immunoprecipitation (MeRIP) and RIP assays were used to analyze the methylation modification and the binding interactions between molecules. BACH1 mRNA level was examined by qRT-PCR. Finally, an animal model of IS was established using middle cerebral artery occlusion (MCAO) to further validate the in-vitro findings. Results Silencing BACH1 alleviated injury in OGD/R-induced SK-N-SH cells. METTL14 and IGF2BP1 cooperatively enhanced BACH1 expression via an m6A-dependent mechanism. Overexpression of BACH1 reversed the protective effects of METTL14 silencing. Moreover, METTL14 inhibited the Nrf2/SLC7A11/GPX4 pathway by stabilizing BACH1. BACH1 downregulation attenuated IS progression in vivo . Conclusion The METTL14/IGF2BP1 complex stabilizes BACH1 mRNA through m6A modification. This leads to suppression of the Nrf2/SLC7A11/GPX4 pathway, promotion of ferroptosis, and ultimately exacerbation of IS.