Deubiquitination-driven adaptive programs in hepatocellular carcinoma: The emerging role of USP22 in hypoxia, metabolic rewiring, and drug resistance

• USP22 coordinates deubiquitination-driven adaptation in HCC. • USP22 integrates hypoxia, metabolism, stemness and drug tolerance. • USP22 targeting requires combination and time-aware strategies. Hepatocellular carcinoma (HCC) is characterized by profound phenotypic plasticity and limited therapeutic durability. Despite the availability of tyrosine kinase inhibitors, chemotherapy, and immune checkpoint inhibitors, most patients eventually develop resistance, often in the absence of clear genetic alterations. This highlights the importance of non-genetic, adaptive mechanisms that enable tumor cells to survive therapeutic and microenvironmental stress. Deubiquitination has emerged as a critical regulatory layer in stress adaptation, yet its role in orchestrating coordinated resistance programs remains underappreciated. Ubiquitin-specific protease 22 (USP22), originally characterized as a component of the SAGA transcriptional complex, is increasingly recognized as a central regulator of adaptive reprogramming in HCC. In this review, we synthesize recent mechanistic and translational studies demonstrating how USP22 integrates hypoxia tolerance, metabolic rewiring, cancer stemness, immune evasion, and drug resistance into a unified adaptive network. We highlight the role of USP22-centered positive feedback loops in converting transient stress signals into stable, drug-tolerant states, thereby driving non-genetic resistance to targeted therapy, chemotherapy, and immunotherapy. Finally, we discuss emerging therapeutic strategies that exploit USP22 dependency through combination and timing-aware interventions, as well as the potential of USP22 as a biomarker for identifying highly adaptive, treatment-refractory HCC. Collectively, these insights position USP22 as a network stabilizer of malignant adaptation and a promising target for overcoming therapeutic resistance in hepatocellular carcinoma.