Pathological role of deubiquitinating enzymes in lung cancer: recent insights and advances

Lung cancer remains the leading cause of cancer-related death worldwide. Following extensive investigations into the mechanisms of lung cancer and targeted therapy, clinical treatment options are now more abundant than ever. However, the overall rates of treatment success and long-term survival remain low among patients with lung cancer, and the prognosis is even poorer for patients with metastatic disease. In this context, a more comprehensive review of the targeted regulatory mechanisms involved in the occurrence and progression of lung cancer could expand the population of patients benefiting from existing clinical treatments and ultimately improve the prognosis of this malignancy. Deubiquitinating enzymes (DUBs) are a specialized class of cellular proteases. These enzymes cleave ubiquitin moieties from substrate proteins or ubiquitin chains, thereby modulating ubiquitination dynamics. Through this catalytic process, DUBs maintain the dynamic balance of ubiquitination within cells. In recent years, accumulating evidence has demonstrated that DUBs serve diverse regulatory functions in multiple molecular events associated with tumorigenesis and malignant progression. Rather than acting through a single mechanism, DUBs participate in tumor progression through multifaceted pathways. In this comprehensive review, we systematically summarize the recent advances in our understanding of the biological functions of DUBs during the pathogenesis and progression of lung cancer. We highlight the mechanistic roles of various DUBs in tumor initiation, development, and metastasis. The topics covered include the regulation of cancer-associated signaling pathways by DUBs, their role in metabolic reprogramming, the DUB-induced modulation of tumor immune responses, the control of cell cycle progression and proliferation by DUBs, as well as other fundamental cellular processes modulated by these enzymes. In addition, we clarify the pathological mechanisms linking DUBs with lung cancer, including upstream regulators and the corresponding downstream molecular signals. Furthermore, we assess the therapeutic potential of these DUBs as candidate therapeutic targets and mediators of drug resistance. This synthesis of the literature provides a strategic framework for identifying clinically relevant DUB targets in lung cancer.