Loss of m6A unmasks a senescence-associated inflammatory program in human microglia

Abstract

Chronic microglial inflammation and cellular senescence are hallmarks of the aging brain, yet the molecular events that lock microglia into durable inflammatory states remain poorly understood. Prior studies using genetic manipulation of METTL3 have implicated the RNA modification N6-methyladenosine (m6A) in senescence. However, because METTL3 also has m6A-independent functions, loss-of-function approaches cannot distinguish whether senescence arises from reduced m6A itself or from broader disruption of METTL3-dependent pathways. This question is further complicated in microglia, where METTL3 has been reported to promote acute inflammatory activation, suggesting that m6A may have context-dependent effects on immune state. Whether sustained reduction of m6A is sufficient to drive microglial senescence has therefore remained unresolved. Here, we show that selective catalytic inhibition of METTL3 with STM2457 lowers global m6A and is sufficient to induce a senescence-like inflammatory state in human HMC3 microglia. This state includes increased senescence-associated {beta}-galactosidase activity, elongated cellular morphology, reduced proliferation, Lamin B1 loss, and remodeling of nuclear architecture. Transcriptomic profiling revealed suppression of mitotic gene programs together with a SASP-like inflammatory output marked by NF-{kappa}B and interferon signatures. Rather than causing broad transposable-element derepression, m6A inhibition promoted cytoplasmic double-stranded RNA accumulation and a selective HERVK-associated response. These findings support a model in which m6A helps preserve microglial homeostasis by limiting immunogenic RNA accumulation and senescence-associated inflammatory remodeling. Together, our study identifies m6A as a safeguard against microglial senescence and suggests that reduced m6A-dependent RNA regulation may contribute to chronic inflammatory remodeling in the aging brain.