Histone lactylation-induced OTUD6B-AS1 promotes progression of hepatocellular carcinoma through forming a positive feedback with HMGB3

Histone lactylation is a recently identified lactate-derived post-translational modification that mechanistically links cellular metabolism to epigenetic regulation. Enrichment of histone lactylation at gene promoters is critical for sustaining the transcription of genes that drive tumor initiation and progression. However, the landscape of histone lactylation–associated long noncoding RNAs (lncRNAs) and their functional roles in hepatocellular carcinoma (HCC) remain largely unexplored. Histone lactylation levels were evaluated in human HCC cohorts with survival follow-up. Histone lactylation-regulated lncRNA profiles were systematically characterized through integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptome sequencing data. The effects of OTUD6B-AS1 on HCC proliferation were examined in vitro and in vivo using CCK-8 assays, colony formation assays, and a nude mouse subcutaneous xenograft model. RNA stability assays were conducted to elucidate the regulatory mechanisms of OTUD6B-AS1 . The interaction between OTUD6B-AS1 and HMGB3 was assessed using dual-luciferase reporter assays. Tumor tissues exhibited significantly elevated histone lactylation levels, which were strongly associated with poor prognosis in HCC patients. Lactylation of histone H3 at lysine 18 (H3K18la)-regulated lncRNA OTUD6B-AS1 promoted HCC proliferation both in vitro and in vivo by enhancing HMGB3 mRNA stability and activating the Wnt/β-catenin signaling pathway. In turn, HMGB3 amplified global histone lactylation and OTUD6B-AS1 expression by intensifying glycolytic activity. The H3K18la/ OTUD6B-AS1 /HMGB3 axis forms a positive feedback loop that drives HCC progression. Targeting histone lactylation and its downstream effectors may represent a promising therapeutic strategy for the management of HCC.