ResiDUBs: A deubiquitinating enzyme-based prognostic model identifies UBXN1 driving sorafenib resistance in liver cancer.

Deubiquitinating enzymes (DUBs) are a class of biological macromolecules with molecular weights ranging from 30 to 150 kDa that play extensive roles in tumor initiation and progression. However, their implications in sorafenib resistance in liver cancer remain incompletely understood. In this study, we identified sorafenib resistance-associated DUBs through weighted gene co-expression network analysis and differential expression profiling. Subsequently, we developed a DUB-based predictive model for liver cancer resistance, designated ResiDUBs, using multivariate Cox regression analysis. This model was employed to assess drug resistance and prognostic outcomes. The ResiDUBs model-constructed based on five DUBs (OTUB1, USP32, USP48, USP49, and UBXN1)-stratified patients into high- and low-risk groups. Patients in the high-risk group exhibited significantly greater sorafenib resistance, poorer prognosis, and hyperactivation of the PI3K/AKT signaling pathway. Multi omics analyses, including single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing, consistently identified UBXN1 as the most prominent resistance-associated gene within the ResiDUBs signature. UBXN1 expression was markedly upregulated in treatment-resistant tumors. Knockdown of UBXN1 sensitizes liver cancer cells to sorafenib and inhibits PI3K/AKT pathway activity. Conversely, overexpression of UBXN1 increases cellular resistance to sorafenib, activates the PI3K/AKT pathway, and induces macrophage polarization toward the M2 phenotype. In vivo experiments further demonstrate that UBXN1 knockdown enhances the sensitivity of liver cancer cells to sorafenib and significantly reduces PI3K/AKT pathway activity. Our findings suggest that targeting UBXN1 may represent a promising therapeutic strategy to overcome sorafenib resistance in liver cancer.