A Novel YTHDF2/SIGMAR1 Axis in Astrocytes Regulates Neuroinflammation and Cognitive Impairment in Diabetic Encephalopathy

Diabetic encephalopathy (DE), a severe complication of diabetes, is characterized by cognitive decline and neuroinflammation, in which astrocytes play a critical role. YTHDF2, an m⁶A reader protein, has been implicated in regulating inflammatory processes. This study investigated the role of astrocytic YTHDF2 in DE pathogenesis. In a mouse model of high-fat diet-induced DE, we observed significant cognitive impairment and hippocampal inflammation. Astrocyte-specific overexpression of YTHDF2 alleviated these deficits, reducing cognitive dysfunction and the levels of pro-inflammatory cytokines IL-1β and IL-6. Both in vivo and in vitro high-glucose models confirmed that YTHDF2 overexpression suppressed astrocyte activation. YTHDF2 negatively regulated SIGMAR1 expression by promoting SIGMAR1 mRNA degradation, which inhibited astrocyte activation and inflammation. Mechanismly, SRAMP, a sequence-based predictor of m⁶A modification sites, identified four high-confidence m⁶A sites (P828, P916, P938 and P979) in SIGMAR1 mRNA. Mutation of P916 m⁶A site could inhibit SIGMAR1 mRNA degradation induced by YTHDF2 overexpression. Our findings demonstrate that astrocytic YTHDF2 attenuates astrocyte activation and neuroinflammation by promoting SIGMAR1 mRNA degradation in DE progression, which may provide a novel treatment strategy for neuroinflammation and cognitive dysfunction in DE.