Deubiquitinating enzymes in pancreatic ductal adenocarcinoma: signaling networks, biomarkers, and mechanism-guided combination strategies

Ubiquitination is a reversible post-translational modification dynamically regulated by ubiquitin ligases and deubiquitinating enzymes (DUBs). By removing or editing ubiquitin chains on substrate proteins, deubiquitinating enzymes regulate protein stability, subcellular localization, signaling-complex assembly, and cellular stress responses. Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked invasiveness, extensive metabolic reprogramming, pronounced therapeutic resistance, and an immunosuppressive microenvironment, highlighting the need for molecularly informed biomarkers and mechanism-guided therapeutic strategies. However, the translational interpretation of DUBs in PDAC remains challenging because DUBs often display broad substrate spectra, context-dependent functions, conserved catalytic domains, and uneven levels of experimental and clinical evidence. Increasing evidence indicates that multiple DUBs regulate PDAC progression and therapeutic resistance through KRAS-RAS/MAPK, Wnt/β-catenin, Hippo-YAP/TAZ, PI3K/AKT/mTOR, Notch, NF-κB, autophagy, metabolism, immune evasion, and metastasis-related programs. In this review, we organize the available evidence according to DUB-substrate axes, ubiquitin linkage types, pathway dependency, model-system support, biomarker feasibility, and therapeutic readiness. We distinguish evidence derived from cell-based assays, animal models, organoids, patient-derived xenografts, patient tissues, public datasets, and clinical cohorts, and classify DUB-centered biomarkers according to their diagnostic, prognostic, predictive, or pharmacodynamic potential. We further summarize DUB-targeting strategies and mechanism-guided combinations with chemotherapy, metabolic intervention, DNA-damage response targeting, and immune checkpoint blockade, while emphasizing inhibitor selectivity, pharmacokinetic and toxicity limitations, resistance mechanisms, and clinical readiness. DUB-centered translation in PDAC should be developed as an axis-based and evidence-ranked framework rather than as a single-target catalogue. The most promising near-term opportunities are likely to arise from DUB-substrate axes with defined mechanisms, measurable biomarker readouts, patient-derived or clinically annotated validation, pharmacodynamic indicators, and rational combination partners. Most DUB-targeted strategies in PDAC remain preclinical and require further validation before clinical implementation. Not applicable.