Knockdown of YTHDF2 mitigates OGD-induced microglial inflammation by preventing m6A-dependent PARP14 degradation.

Neuroinflammation is a key pathological factor in ischemic brain diseases, contributing to the initiation and progression of these conditions. The function of the m6A reader protein YTHDF2 in regulating neuroinflammation across various neurological contexts. To elucidate the role and regulatory mechanism of YTHDF2 in inflammation under ischemic-like conditions, this study employed an in vitro model, exposing microglia to oxygen-glucose deprivation (OGD) to mimic the stress environment. And through YTHDF2 knockdown, we investigated its effect on OGD-induced inflammation. The results demonstrated that YTHDF2 knockdown significantly suppressed the expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), in OGD-treated microglia. Mechanistic analysis revealed that YTHDF2 interacts with Parp14 mRNA under OGD conditions, reducing its RNA stability via m6A-dependent mechanisms, which in turn decreases Poly (ADP-ribose) polymerase family, member 14 (PARP14) protein expression. Additionally, YTHDF2 knockdown after OGD promoted a PARP14-driven phenotypic switch in microglia from the pro-inflammatory M1 state to the anti-inflammatory M2 state, resulting in diminished inflammation. These findings offer new insights into the regulatory function of YTHDF2 in OGD-induced microglial inflammation and propose m6A modification as a potential therapeutic target for alleviating neuroinflammation.