Targeted proteoform degradation for precision drug design, delivery, and therapy

Ubiquitin-proteasome system (UPS)-mediated targeted protein degradation (TPD) is a central mechanism of maintaining protein homeostasis, which is closely associated with multiple diseases. Proteolysis-targeting chimeras (PROTACs) represent a major platform in TPD research and have demonstrated advantages relative to traditional intervention methods, such as small-molecule inhibitors, particularly in expanding the scope of targetable proteins. PROTACs have significant scientific merits in drug discovery and development. Currently, TPD still focuses on the conventional 'protein' level. However, the development of proteoform and proteoformics has enriched the deep understanding of the structural and functional diversities of a conventional protein. Targeted proteoform degradation (TPfD) has been proposed as an approach to more accurately recognize subtle structural and functional alterations within canonical proteins, thereby potentially improving precision drug delivery. Pathology-specific proteoform-based TPfD may facilitate the design of more precisely targetable degradation tools, potentially shifting strategies from general targeting toward more refined clearance. This review discusses the concept, mechanism, and developmental landscape of protein-based TPD and its core tool PROTACs, while systematically elaborating on the limitations of traditional TPD technologies - particularly the challenges associated with distinguishing functionally heterogeneous proteoforms. Thus, this review proposes the innovative concept of proteoform-based TPfD, detailing its technical foundations (rooted in proteoformics), core design methodologies (including ligand optimization, linker system engineering, and E3 ligase selection), and key applications in disease molecular typing, personalized drug development, and dynamic therapeutic regimen optimization. It further explores the potential role of TPfD in advancing precision medicine and discusses how proteoform-oriented strategies may contribute to refining therapeutic approaches for complex diseases.