Translational evaluation of BUB1B as a precision medicine biomarker for hepatocellular carcinoma.

[UNLABELLED] Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers, characterized by late-stage diagnosis and poor prognosis due to insufficient biomarkers for early detection and personalized therapy. This study comprehensively investigated BUB1B, a spindle assembly checkpoint component, as a precision medicine biomarker in HCC through integrative multi-omics analysis and clinical validation. Pan-cancer analysis using The Cancer Genome Atlas (TCGA) revealed significant BUB1B upregulation across 19 tumor types, with robust overexpression in HCC ( < 0.05). High BUB1B expression independently predicted poor overall survival (hazard ratio = 1.39, 95% confidence interval: 1.20–1.63,  < 0.001) and correlated with tumor size, Barcelona Clinic Liver Cancer (BCLC) stage, Ki-67 index, and alpha-fetoprotein (AFP) levels. BUB1B expression strongly associated with genomic instability markers including homologous recombination deficiency and microsatellite instability (all  < 0.001). Immune profiling revealed paradoxical enrichment of activated T cells yet elevated Tumor Immune Dysfunction and Exclusion (TIDE) scores ( < 0.001), suggesting immune escape and potential resistance to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Drug sensitivity analysis identified high BUB1B expression as predictive of enhanced sensitivity to sorafenib, paclitaxel, and doxorubicin. Clinical validation in an independent cohort confirmed BUB1B overexpression, cytoplasmic localization, and association with worse survival ( = 0.044). Mechanistic studies using selective BUB1B inhibitors demonstrated comprehensive mitogen-activated protein kinase (MAPK) pathway regulation, with significant suppression of HRAS (60% reduction), extracellular signal-regulated kinase 1/2 (ERK1/2) (40–60% reduction), and p38 isoforms (30–60% reduction) (all  < 0.05).These findings establish BUB1B as a clinically actionable biomarker for risk stratification and precision therapeutics in HCC management.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1038/s41598-026-36364-x.