Opportunities and challenges of PROTAC in the treatment of protein-driven diseases

Targeted protein degradation (TPD) has transformed the landscape of drug discovery by exploiting the ubiquitin-proteasome system (UPS) to eliminate, rather than inhibit, pathogenic proteins. This paradigm shift enables access to a vast array of previously “undruggable” targets and offers new therapeutic opportunities across diverse diseases. Among the available approaches, proteolysis-targeting chimera (PROTAC) have rapidly advanced from concept to clinical evaluation. Here we highlight the unique advantages of PROTAC in disease treatment and target identification, and examine emerging solutions to address key challenges such as pharmacokinetics, E3 ligase diversity, and selectivity. Together, these advances define a new era of precision therapeutics based on the controlled elimination of disease drivers.