Abstract
BACKGROUND: Targeted protein degradation (TPD) is a novel protein modulation strategy distinct from traditional inhibitors. Its core mechanism involves labeling proteins of interest to initiate endogenous protein clearance pathways, mainly including the ubiquitin-proteasome system (UPS) pathway and the lysosomal pathway. TPD has emerged as a promising therapeutic approach for various diseases, but its clinical translation and therapeutic efficacy are hindered by limitations of TPD formulations such as poor bioavailability and off-target effects.. MAIN BODY: This review first elaborates on the different types of TPD strategies and their respective implementation mechanisms. Subsequently, it summarizes the current research status of TPD in major disease fields, including tumor therapy (with a focus on the regulation of key proteins such as Bruton Tyrosine Kinase, Androgen Receptor, Estrogen Receptor, and cell cycle-related proteins), neurodegenerative diseases, and inflammatory/immune diseases. Additionally, the potential of drug delivery systems to address the aforementioned limitations of TPD formulations is discussed, as they may substantially enhance TPD therapeutic efficacy. CONCLUSIONS: This review provides a comprehensive overview of current TPD types, their research progress in different diseases, and strategies for effective application of TPD. It is expected to offer valuable guidance for the development of TPD formulations and promote their clinical translation.