Histone modification-regulated LncRNA DLEU1 interacts with ASCC2/ALKBH3 complex to drive DNA repair, antioxidant homeostasis and glucose metabolism in gastric cancer

Abstract Background Long non-coding RNA (lncRNA) DLEU1 has been implicated in tumorigenesis, yet its mechanistic role in gastric cancer (GC) remains elusive. Methods We investigated the epigenetic regulation and oncogenic function of DLEU1 in GC through chromatin immunoprecipitation, RNA-protein interaction assays, and functional analyses in organoids and xenograft models. The molecular mechanisms underlying DLEU1-mediated DNA repair and metabolic adaptation were elucidated using western blotting, quantitative RT-PCR, and luciferase reporter assays. Results DLEU1 was significantly upregulated in GC, driven by H3K27 acetylation and H3K4 methylation. Mechanistically, DLEU1 promoted DNA repair by facilitating ASCC2 nuclear translocation and its interaction with ALKBH3, thereby stabilizing E2F1 mRNA. In turn, E2F1 directly activated G6PD transcription, leading to enhanced NADPH production, redox homeostasis, and glucose metabolism. Functionally, co-targeting DLEU1 and ASCC2 synergized with G6PD inhibition, significantly impairing GC cells viability and tumor growth. Conclusion Our findings establish DLEU1 as a key oncogenic lncRNA in GC, orchestrating DNA repair, redox balance, and metabolic adaptation via the ASCC2-ALKBH3-E2F1-G6PD axis. Targeting this pathway may provide a promising therapeutic strategy for overcome GC chemoresistance.