HAT1 regulates glioblastoma cell proliferation and membrane lipid remodeling through ALDH2

Abstract Glioblastoma (GBM) is the most aggressive and lethal form of primary brain cancer in adults, characterized by rapid cell proliferation, resistance to therapy, and poor patient outcomes. While epigenetic dysregulation is increasingly recognized in glioma pathogenesis, the role of Histone Acetyltransferase 1 (HAT1) in GBM remains largely undefined. Here, we demonstrate that HAT1 expression is progressively reduced in high-grade gliomas of human tissue microarrays as well as in glioma cell lines with increased malignancy. We show that HAT1 depletion in glioma cells significantly enhances cell proliferation and membrane fluidity specifically in aggressive GBM subtypes (A172 and U87). Integrated transcriptomics and lipidomics analyses revealed upregulation of lipid metabolism pathways, including enhanced glycerophospholipid biosynthesis, alongside a marked induction of aldehyde dehydrogenase 2 (ALDH2) expression in HAT1-deficient cells. In contrast, HAT1 re-expression suppressed proliferation, restored membrane properties, and downregulated ALDH2. Subcutaneous xenograft models confirmed that HAT1 loss accelerates tumor growth, while HAT1 overexpression restrains it. Notably, knockdown of ALDH2 in HAT1-depleted GBM cells reversed the hyperproliferative and high-membrane-fluidity phenotype, identifying ALDH2 as a key downstream effector. Collectively, our data uncover a novel HAT1–ALDH2–lipid remodeling axis that regulates GBM cell proliferation and membrane plasticity, positioning HAT1 as a suppressor of GBM aggressiveness and highlighting this pathway as a potential axis for prognostic and therapeutic exploitation in GBM.