TMET-31. Epitranscriptomic Control of Glioblastoma Malignancy: NAT10/ac4C-Driven LPL mRNA Stabilization Reprograms Lipid Metabolism

Abstract Glioblastoma (GBM) represents the most malignant primary intracranial tumor, with its pathogenesis remaining incompletely understood. Leveraging our established brain organoid-GBM co-culture model that recapitulates tumor proliferation and invasive behavior, we identified N-Acetyltransferase 10 (NAT10) as a key molecular driver of GBM invasiveness through comparative sequencing of invasive versus non-invasive tumor populations. We demonstrate that: Aberrant ac4C RNA modification and elevated NAT10 acetyltransferase expression are prevalent in gliomas compared to normal brain tissue. NAT10 knockdown suppresses GBM proliferation, invasion, and glioblastoma stem cell (GSC) self-renewal capacity. Lipoprotein lipase (LPL) is a critical downstream target of NAT10-mediated ac4C modification. We therefore propose the mechanistic hypothesis: NAT10 drives tumor progression by catalyzing aberrant ac4C modification, thereby enhancing the mRNA stability and translation efficiency of LPL. This leads to dysregulated lipid accumulation within GBM cells. Pharmacological inhibition of NAT10 with Remodelin represents a promising therapeutic strategy targeting this pathway. This project aims to employ integrated multi-omics sequencing to elucidate the molecular mechanisms by which the NAT10/ac4C axis promotes glioma malignancy. We seek to define novel epitranscriptomic regulatory aberrations in GBM pathogenesis, establishing a foundational framework for developing targeted GBM therapies.