Crontonylation regulatory factor DPF2 promotes the occurrence of hepatocellular carcinoma by regulating glycosphingolipid metabolism

Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide, characterized by poor prognosis and limited therapeutic options. Emerging evidence indicates that both lipid metabolism and post-translational modifications, particularly lysine crotonylation (Kcr), play critical roles in tumor progression. Methods In this study, we employed Mendelian randomization, generalized summary-data-based Mendelian randomization, and transcriptomic analyses to explore the causal roles of Kcr regulatory genes in HCC. Results Among 16 Kcr regulators, DPF2 was identified as significantly associated with increased HCC risk. Mediation analysis further revealed that DPF2 may promote HCC development by downregulating glycosyl-N-behenoyl-sphingadienine (d18:2/22:0), a glycosphingolipid with tumor-suppressive properties, accounting for 13.5% of its effect.Functional enrichment and gene set variation analysis demonstrated that DPF2 expression was linked to lipid metabolic processes, histone modification pathways, and inflammatory responses. Although some associations did not meet strict FDR correction thresholds, the findings were consistent with transcriptomic validation and previous literature, indicating potential biological relevance. Conclusion Overall, this study provides novel evidence supporting the role of DPF2 in the lipid metabolism–Kcr axis of HCC and suggests its value as a potential biomarker or therapeutic target. Further in vivo and in vitro experiments are needed to elucidate the underlying mechanisms.