<scp>FTO</scp> Fuels Aβ _1–40 ‐Induced Retinal Pigment Epithelium Cell Injury Associated With Pyroptosis by Erasing <scp>m6A</scp> Methylation of the <scp>lncRNA</scp> <i>Neat1</i>

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.