Modulators of the ubiquitin–proteasome system from natural products: chemical structures and their potential for drug discovery

Covering: up to 2024The ubiquitin-proteasome system (UPS) plays a key role in regulating intracellular protein degradation and maintaining cellular homeostasis. Within the UPS, target proteins are polyubiquitinated through sequential reactions catalyzed by ubiquitination-related enzymes. These ubiquitinated proteins are then recognized and degraded by the 26S proteasome. Deubiquitinating enzymes cleave the formed polyubiquitin chains and regulate protein degradation, thereby contributing to precise regulation of the system. Dysregulation of the UPS is associated with cancer, immune disorders, and neurodegenerative diseases, making it a potential target for drug discovery. To date, a variety of natural products that target the UPS have been discovered and used in pharmaceutical development, and these compounds have provided important insights into the molecular mechanisms of UPS regulation. This review describes natural products that inhibit protein degradation in the UPS and activate protein degradation mediated by the 20S proteasome, thus clarifying their mechanisms of action and exploring their potential applications as therapeutic agents.