Single-Cell RNA-seq Reveals Deubiquitination Genes as Prognostic Markers in Hepatocellular Carcinoma

<h4>Background</h4>Hepatocellular carcinoma (HCC) carries a dismal prognosis, yet the contribution of deubiquitination-an essential posttranslational regulator-to its progression remains poorly defined.<h4>Methods</h4>Single-cell RNA-seq profiles of 13 treatment-naïve HCC tumors were integrated with 374 TCGA and 243 ICGC bulk RNA-seq cohorts. Deubiquitinase (DUB) activity was quantified per cell with AUCell; pathway enrichment was performed with clusterProfiler. A LASSO-Cox machine learning pipeline was used to build a DUB-based risk signature, which was cross-validated internally and externally by time-dependent ROC analysis.<h4>Results</h4>Malignant cells exhibited divergent DUB transcription relative to immune compartments (myeloid, B). DUB-high neoplastic subsets displayed heightened inflammatory and IFN-<i>γ</i> signaling, concordant with brisk immune infiltration. A 78-gene prognostic index robustly stratified survival in discovery and replication cohorts.<h4>Conclusions</h4>This study highlights the role of deubiquitination in HCC progression and its potential as a prognostic biomarker. The developed model could serve as a valuable tool for patient stratification and personalized treatment strategies, although further experimental validation is needed to confirm these findings.