METTL3 inhibition alleviates neuroinflammation and apoptosis by reducing ETV4 m6A modification.

Abstract

Intracerebral hemorrhage (ICH) triggers devastating secondary brain injury driven by maladaptive microglial activation and neuroinflammation. While N6-methyladenosine (m6A) RNA methylation influences inflammation, its spatiotemporal regulation in ICH microglia remains unclear. Here, we identified METTL3 as a key epigenetic driver that promotes neuropathology post-ICH. Our analyses revealed that upregulated METTL3 expression in activated microglia in ICH model mice was correlated with increased global m6A levels. Functional studies have demonstrated that METTL3 depletion attenuates the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), suppresses NF-κB activation, and reduces apoptosis in microglia. Mechanistically, MeRIP-seq and RNA-seq identified the transcription factor ETV4 as a METTL3 target, where METTL3-mediated m6A modification of the ETV4 3'-UTR recruits the reader IGF2BP2 to increase mRNA stability. This axis drives NF-κB-mediated inflammation and caspase-3-dependent apoptosis. Overall, our work reveals the role of METTL3 in sustaining neuroinflammation and inducing apoptosis via m6A/ETV4 stabilization and suggests that METTL3 inhibition is a promising strategy for ameliorating ICH injury.