ANP32E drives lung adenocarcinoma progression via GSK3β-mediated glycolytic reprogramming

Lung adenocarcinoma (LUAD), a leading cause of cancer mortality, involves incompletely understood epigenetic-metabolic crosstalk. We identified ANP32E as a key regulator through multi-omics (TCGA, scRNA-seq) and clinical analyses, finding its overexpression correlates with poor prognosis. Functionally, ANP32E knockdown suppressed proliferation, migration, and glycolysis in LUAD cells (A549/H1975) and attenuated xenograft growth, while overexpression promoted tumorigenesis. Mechanistically, ANP32E transcriptionally upregulates histone demethylase KDM3B, reducing repressive H3K9me2 marks at the EGFR promoter to enhance EGFR transcription. This activates PI3K/AKT signaling, inducing inhibitory GSK3β phosphorylation. Combined with ANP32E-mediated GSK3β suppression, this dual inactivation liberates oncogenic glycolysis. Crucially, KDM3B silencing or EGFR inhibition (Cetuximab) abrogated ANP32E-driven phenotypes. High-throughput screening identified Penta-O-galloyl-β-D-glucose (PGG) as an ANP32E-targeting compound, with molecular dynamics confirming binding. PGG dose-dependently inhibited the ANP32E/KDM3B/EGFR axis in vitro and suppressed tumor growth in vivo. Thus, ANP32E drives LUAD progression via KDM3B/EGFR-mediated GSK3β inactivation, representing a prognostic biomarker and therapeutic target validated by PGG.