Targeting the KAT7/H3K14ac/RAC2 Axis Mediates OXPHOS to Promote Stemness Maintenance and Malignancy in Glioblastoma

Abstract

ABSTRACT Glioblastoma multiforme (GBM), the most lethal type of primary brain tumor, exhibits profound metabolic plasticity driven by glioma stem cells (GSCs), which sustain therapeutic resistance and tumor recurrence. Here, we elucidate a novel epigenetic‐metabolic axis mediated by the histone acetyltransferase KAT7 that orchestrates oxidative phosphorylation (OXPHOS) dominance in GSCs. Through a multi‐omics analysis, we demonstrated that KAT7 is preferentially upregulated in GBM, particularly in the classical subtype and in GSC‐enriched populations, where it activates Rac family samll GTPase 2 (RAC2) expression via H3K14 acetylation of its promoter. Mechanistically, KAT7‐mediated RAC2 upregulation triggers PAK1/2/3 phosphorylation, increasing tricarboxylic acid cycle (TCA) and ATP production. Genetic ablation of KAT7 impairs GSCs self‐renewal, induces apoptosis, and suppresses tumor growth in orthotopic xenograft models. Conversely, KAT7 overexpression or pharmacological activation of the KAT7–RAC2 axis restores metabolic fitness and malignant phenotypes. Notably, the small‐molecule inhibitor WM‐3835, which targets KAT7, exhibits potent anti‐GBM efficacy by disrupting H3K14ac and mitochondrial respiration, leading to prolonged survival in mice. Our study identifies KAT7 as a master regulator of GSCs metabolism, revealing an actionable therapeutic target in GBM progression. Targeting the KAT7–RAC2–PAK axis may represent a precise strategy to overcome metabolic plasticity‐driven therapeutic resistance in this recalcitrant malignancy.