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

Abstract

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.