FTO Fuels Aβ 1–40 ‐Induced Retinal Pigment Epithelium Cell Injury Associated With Pyroptosis by Erasing m6A Methylation of the lncRNA Neat1

ABSTRACT Retinal pigment epithelium (RPE) degeneration in association with inflammation is a key feature of age‐related macular degeneration (AMD) pathology. Amyloid β (Aβ) in drusenoid deposits, the hallmark of AMD, is a critical initiating component that causes RPE cell damage through the activation of the NLR family pyrin domain containing 3 (NLRP3)‐mediated inflammatory response. Epigenetic mechanisms have been reported to contribute to the pathogenesis of AMD. However, the extent to which epigenetic modifications regulate Aβ‐mediated RPE inflammatory damage and cell death remains unclear. N6‐methyladenosine (m6A) is the most abundant RNA epigenetic regulation in eukaryotes. Herein, based on bioinformatics analysis, we identified that fat mass and obesity‐associated protein (FTO) acts as an essential epigenetic regulator in Aβ 1–40 ‐mediated RPE inflammatory cell death. Activation of NLRP3 inflammasome‐related RPE pyroptosis was evident through enhanced NLRP3, gasdermin D immunoreactivity, increased caspase‐1 cleavage, elevated IL‐1β secretion, and higher LDH activity. Deletion of FTO resulted in the inhibition of RPE pyroptosis in vitro and in vivo. Mechanistically, methylated RNA immunoprecipitation (MeRIP) combined with RNA‐seq demonstrated that long noncoding RNA (lncRNA) Neat1 served as a downstream target of FTO, with FTO knockdown suppressing Neat1 expression in an m6A‐dependent manner. Neat1 depletion deactivated inflammatory factors, thereby hindering Aβ 1–40 ‐induced RPE pyroptosis. Furthermore, FTO silencing attenuated Neat1 ‐mediated pyroptosis, resulting in compromised retinal structure and function. These findings suggest that the FTO‐ Neat1 ‐NLRP3 network provides potential targets to treat AMD while expanding our understanding of the role of epigenetically modified lncRNAs in Aβ‐driven RPE injury.