Targeting the Ubiquitin–Proteasome System for Cancer

Ubiquitin is a highly conserved small molecule that exists in large quantities in eukaryotic cells and plays a crucial role in protein quality control by phagocytosis and degradation of ubiquitin-modified proteins. The abnormal expression of the ubiquitin-proteasome system (UPS) in cancer leads to the abnormal expression of ubiquitin ligases and ubiquitin-binding enzymes, resulting in the abnormal accumulation of ubiquitinated proteins. Consequently, UPS dysregulation can contribute to tumor initiation, progression, and resistance to therapy. While proteasome inhibitors have shown clinical success, comprehensive reviews integrating upstream UPS components and their therapeutic potential are lacking. This paper reviews the composition of the UPS, its tumor-promoting mechanisms, as well as the small molecule inhibitors and proteasome inhibitors based on this system, including their mechanisms of action and adverse effects, and explores their clinical advances in the treatment of cancer. This review provides a valuable framework for developing next-generation anti-cancer therapies and establishes the UPS as a critical therapeutic target for precision oncology.