The degradation revolution: harnessing targeted protein degradation for the treatment of human diseases.

Targeted protein degradation (TPD) redefines therapeutic strategies by overcoming the key limitations of traditional occupancy-driven pharmacology. TPD introduces a paradigm shift by using the cell’s intrinsic degradation systems—primarily the ubiquitin–proteasome system (UPS), as well as lysosomal and autophagy pathways—to eliminate disease-causing proteins. Here, we first summarize the research progress of the most advanced TPD platform, proteolysis-targeting chimeras (PROTACs). While most TPD strategies currently rely on a few well-characterized E3 ligases, such as CRBN and VHL, ongoing research aims to expand the ligase repertoire to increase tissue specificity and overcome resistance. Therefore, we also characterized alternative TPD platforms, such as lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), and ribonuclease-targeting chimeras (RIBOTACs), which exploit lysosomal and autophagy pathways, broadening the ability of TPD to reach extracellular and aggregated proteins. Moreover, the application of TPD in oncology, neurodegeneration, immunology, and infectious diseases, with several agents advancing into clinical trials, has also been concluded. On the other hand, the key challenges of TPD remain, including improving bioavailability, minimizing off-target effects, and understanding resistance mechanisms. Overall, as novel chemistries and delivery strategies continue to evolve, TPD represents a powerful and versatile modality with the potential to radically expand the druggable proteome and address unmet medical needs across a wide range of diseases.