ABCF1-K430-Lactylation promotes HCC malignant progression via transcriptional activation of HIF1 signaling pathway.

Lysine lactylation plays critical roles in various diseases, including cancer. Our previous study showed that lactylation of non-histone ABCF1 may be involved in hepatocellular carcinoma (HCC) progression. In this study, we evaluated the prognostic value of ABCF1-K430la in HCC using immunohistochemical staining and performed amino acid point mutations, multi-omics crossover, and biochemical experiments to investigate its biological role and underlying mechanism. Additionally, we performed molecular docking on lactylation sites. ABCF1-K430la was highly expressed in HCC tissues and correlated with poor patient prognosis. Functionally, ABCF1-K430la promoted HCC growth and lung metastasis. Mechanistically, upon lactylation, E2 ubiquitin ligase activity of ABCF1 remained unaffected, and ABCF1 entered the nucleus, bound to the KDM3A promoter to upregulate its expression, and activated the KDM3A-H3K9me2-HIF1A axis, challenging the notion that ABCF1 functions exclusively in cytoplasmic protein translation. Notably, we discovered the existence of a lactate-ABCF1(430Kla)-HIF1A-lactate in HCC. A small-molecule drug screen targeting ABCF1-K430la revealed that tubuloside A inhibits ABCF1-K430la and suppresses HCC development. These findings demonstrate that elevated ABCF1-K430la expression promotes HCC development, suggesting it as a potential prognostic biomarker and therapeutic target for HCC.