Deubiquitinases as novel therapeutic targets in colorectal cancer

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality and is the third most prevalent malignant tumor in the world. In recent years, the key role of protein post-translational modifications, especially ubiquitination and deubiquitination modifications, in tumorigenesis and progression has gradually been revealed. Deuubiquitinating Enzymes (DUBs) play an important role in CRC cell proliferation, apoptosis, autophagy, immune escape, and chemotherapy resistance by removing ubiquitin chains from proteins, regulating protein stability, activity, and subcellular localization. Research has shown that DUBs such as USP7, USP10, and USP22 promote the progression and metastasis of CRC by stabilizing key tumor associated proteins such as β-catenin, p53, and c-Myc, activating signaling pathways such as Wnt/β-catenin and ERK/MAPK. In addition, DUBs exacerbate malignancy in the tumor microenvironment (TME) by regulating inflammatory responses, immune escape, and polarization of tumor associated macrophages. Meanwhile, DUBs are closely related to chemotherapy resistance, leading to decreased drug sensitivity by maintaining the stability of drug targets or enhancing anti-apoptotic protein function. At present, small molecule inhibitors targeting DUBs have made certain progress, such as USP7 inhibitor P5091 and USP14 inhibitor IU1, providing new directions for the treatment of CRC. However, clinical applications still face challenges such as selectivity and safety concerns. In summary, in-depth research on the molecular mechanisms of DUBs in CRC, the development of more efficient and specific targeted inhibitors, and the exploration of their combined application with other therapeutic methods are expected to provide new strategies for the diagnosis and treatment of CRC.