Strategic selection of TPD technologies based on disease pathology: from mechanistic diversity to clinical implementation

Targeted protein degradation (TPD) offersa way to remove disease-associated proteins rather than only inhibit their activity. Its modalities include heterobifunctional degraders, molecular glues, and lysosome-directed strategies, which differ in their mechanisms and accessible substrates. This review examines how disease pathology can guide TPD selection across cancer, neurodegenerative diseases, metabolic syndrome, autoimmune diseases, and infectious diseases. We compare these approaches according to target localization, protein conformation or aggregation state, and the availability of cellular degradation machinery. Representative preclinical studies and clinical programs illustrate both their potential and the limits of current evidence. Clinical translation remains constrained by tissue delivery, pharmacokinetic properties, target and effector selectivity, acquired resistance, and long-term safety. Molecular design and delivery strategies may help address these barriers, but target degradation must be distinguished from demonstrated therapeutic benefit. A pathology-guided framework can therefore support candidate selection and experimental design, while its clinical utility requires validation in specific disease settings.