Targeting ubiquitination in disease and therapy.

Ubiquitination, a critical posttranslational modification (PTM), involves the enzymatic covalent attachment of ubiquitin to target proteins. This process is fundamental for maintaining cellular homeostasis and regulating key biological functions. The ubiquitination pathway, orchestrated by ubiquitin and its associated enzymes, offers remarkable versatility, acting as a cellular sentinel to ensure precise spatiotemporal control of essential molecular processes. Importantly, the components and mechanisms of ubiquitination can be finely tuned in various ways. Dysregulation of this system can disrupt normal biological processes and contribute to the development of various serious human diseases. These findings underscore the importance of investigating ubiquitination to understand disease mechanisms and develop effective treatment strategies. In this review, we summarize the historical developments and key milestones in ubiquitination research, with a focus on its roles in both health and disease. We explore the components and mechanisms involved, the relevant signaling pathways and their crosstalk, and the multilayered regulatory functions of ubiquitination under physiological and pathological conditions. The pathological contexts discussed include cancer, neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, autoinflammatory disorders and developmental disorders. Enhancing our understanding of ubiquitination could provide novel insights into disease pathogenesis and identify new therapeutic targets. We also highlight emerging strategies for cancer treatment, such as proteolysis-targeting chimeras (PROTACs) and molecular glues. Furthermore, we review therapeutic targets and recent progress in clinical research, including ongoing clinical trials and FDA-approved drugs, aimed at leveraging the ubiquitination pathway for disease treatment.