<p>Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and current therapies offer limited efficacy for many patients. GSK6853, a selective inhibitor of the BRPF1, has shown promising anticancer activity in preclinical studies. However, its therapeutic potential and underlying molecular mechanisms in NSCLC remain uncharacterized. We evaluated the antiproliferative effects of GSK6853 on A549 and H1975 using CCK-8 and colony formation assays. Cell cycle distribution was analyzed by flow cytometry. Annexin V/PI method was performed to detect the rate of apoptosis. Transcriptomic changes induced by GSK6853 were assessed via RNA sequencing, followed by functional enrichment analysis and protein–protein interaction (PPI) network construction. Hub gene identification and pathway predictions were performed using bioinformatics tools. Western blotting was used to validate key protein expression changes. GSK6853 significantly inhibited the proliferation of A549 and H1975 cells in a dose-dependent manner and induced G0/G1 cell cycle arrest and apoptosis. RNA-seq analysis revealed that GSK6853 downregulated genes involved in DNA replication, homologous recombination, and base excision repair pathways. CCNA2 (Cyclin A2) emerged as a central hub gene among the downregulated targets. Western blotting confirmed that GSK6853 suppressed CCNA2 expression via inhibition of the JAK2/STAT3 signaling pathway. Clinical database analysis further showed that CCNA2 is highly expressed in LUAD tissues and its overexpression correlates with poor overall and disease-free survival.&#xa0;Our findings demonstrate that GSK6853 exerts potent antiproliferative effects in NSCLC by disrupting JAK2/STAT3 signaling pathway and suppressing CCNA2-mediated cell cycle progression, and further stimulates apoptosis. These results highlight GSK6853 as a promising therapeutic candidate for lung adenocarcinoma and support further preclinical and clinical evaluation.</p>