Unraveling the prognostic significance and molecular mechanisms of HKDC1 in cancer via integrated multi-omics and experimental validation.

[BACKGROUND] HKDC1 (Hexokinase Domain Containing 1), a recently identified member of the hexokinase family, has emerged as a potential oncogene with significant involvement in tumor progression, immune evasion, and cellular metabolism.

[METHODS] A pan-cancer analysis was performed using TCGA, GTEx, and TIP databases. In vitro experiments, including qPCR, Western blot, CCK-8 assay, scratch assay, colony formation, and transwell assays, were conducted to evaluate HKDC1's role in cancer.

[RESULTS] Bioinformatics study analyses revealed HKDC1 overexpression in 8 malignancies, correlating with a poor prognosis. Multi-dimensional analyses delineated HKDC1's immunomodulatory role, demonstrating pan-cancer correlations with immunoregulatory genes and bidirectional associations with tumor stemness. Single-cell analyses in gastric cancer identified significant interactions between HKDC1 +Mali cells and endothelial cells, fibroblasts, and immune cells, suggesting HKDC1 + malignant cells regulate immune responses and promote tumor growth. Functional validation showed HKDC1 knockdown suppressed GC invasion. Epigenetically, HKDC1 regulates H3K18 lactylation to activate VCAM1, thereby driving gastric cancer proliferation.

[CONCLUSION] In summary, our pan-cancer analysis identifies HKDC1 as a novel biomarker for prognosis and immunotherapy response. HKDC1 drives metabolic reprogramming via glycolysis and immune evasion by suppressing T-cell activity. In GC, HKDC1 promotes H3K18 lactylation, upregulating VCAM1 to enhance tumor progression.