Autophagosome degraders: a novel therapeutic strategy with broad application potential in human diseases

Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverages the autophagy-lysosome pathway for the clearance of challenging substrates that often exceed proteasomal capacity. These substrates include large protein aggregates, multi-protein complexes, and even entire organelles. This review synthesizes key advances in the development of autophagy-based degraders since 2022, highlighting their therapeutic potential through exemplar applications. We discuss their utility in oncology, neurodegenerative disorders, and inflammatory/cardiometabolic diseases. These novel modalities have demonstrated potent, selective, and durable substrate elimination in vivo, successfully overcoming resistance mechanisms associated with traditional occupancy-driven inhibition. Finally, we summarize the general workflow for developing autophagy-based degraders, outline the current challenges and future directions in this field, and aim to promote fundamental mechanistic studies and innovative medicinal chemistry research, thereby accelerating the clinical translation of autophagy-targeting degraders for the treatment of various human diseases.