Histone H3K9 lactylation promotes hepatocellular carcinoma progression by activating LUC7L2 to mediate SPINK13 mRNA degradation

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, yet the contribution of histone lactylation to its progression remains unclear. Histone H3K9 lactylation (H3K9la) has recently emerged as a metabolic–epigenetic mark linking glycolytic reprogramming to transcriptional regulation. We integrated histone modification profiling, transcriptome assays, RNA–protein interaction analyses, and in vitro and in vivo functional experiments to investigate the role of H3K9la in HCC. Molecular and cellular assays included qPCR, Western blotting, ChIP-qPCR, RIP, RNA stability analysis, and functional rescue. Xenograft mouse models were used to validate mechanistic findings. H3K9la levels were elevated in HCC tissues and cell lines and positively correlated with expression of the RNA-binding protein LUC7L2. Inhibition of glycolysis or lactylation suppressed LUC7L2 expression and reduced tumor cell proliferation, migration, and invasion, while promoting apoptosis. Mechanistically, H3K9la activated LUC7L2 transcription, which in turn bound to and destabilized SPINK13 pre-mRNA, repressing its tumor-suppressive function. Overexpression of SPINK13 inhibited HCC cell growth by inducing G1-phase arrest and reducing AKT phosphorylation, whereas its knockdown rescued the inhibitory effects of LUC7L2 silencing. In vivo, blockade of lactylation suppressed tumor growth and downregulated LUC7L2, an effect reversed by SPINK13 silencing or LUC7L2 overexpression. Our findings establish a novel H3K9la–LUC7L2–SPINK13 regulatory axis that links lactate metabolism to post-transcriptional gene silencing and malignant progression in HCC. Targeting this pathway provides a promising epigenetic-metabolic therapeutic strategy.