Advances in molecular biology and proteomics have revealed the central role of dysregulated proteins in driving human disease [1]. As a result, eliminating or disabling pathogenic proteins has become a cornerstone of modern drug discovery. Traditional small-molecule therapeutics typically act by binding to functional pockets on target proteins to inhibit activity [2]. For instance, tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have significantly improved survival in patients with chronic myeloid leukemia (CML) [3]. Nonetheless, the vast majority of proteins—estimated at over 80 % of the human proteome—lack accessible ligandable sites and remain beyond the reach of conventional inhibitors [4]. Additionally, small molecules often engage off-targets, contributing to toxicity and resistance. These limitations are especially problematic in multifactorial diseases such as cancer and neurodegeneration, where perturbations in complex protein networks require broader therapeutic reach [5].
Targeted protein degradation (TPD) provides a paradigm-shifting strategy by redirecting endogenous degradation machinery—primarily the ubiquitin-proteasome system and lysosomal-autophagy pathways—to selectively remove disease-relevant proteins [6]. Unlike occupancy-driven inhibitors that require sustained high-affinity engagement, TPD relies on event-driven mechanisms where brief binding suffices to trigger irreversible degradation [7]. This mechanism enables potent efficacy at low doses and allows for degradation of non-enzymatic scaffolds and scaffolding functions inaccessible to classical inhibitors.
Over the past two decades, TPD has evolved into a diverse and modular platform encompassing proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), and other emerging modalities (Fig. 1). These strategies vastly expand the druggable proteome and are increasingly being translated into clinical applications.
In this review, we systematically trace the developmental trajectory and research advances of TPD technologies. First, we begin with the ubiquitin-proteasome system and the lysosomal-autophagic pathway, elucidating their molecular mechanisms and biological foundations as core degradation pathways, thereby establishing a framework for understanding TPD’s mode of action. Subsequently, we focus on summarizing the design principles, advantages, and latest clinical advances of major technical platforms. These include increasingly mature bifunctional molecules like PROTACs, MGs that induce protein interactions via single small molecules, antibody-conjugated degradation strategies, and various emerging autophagy-related approaches (e.g., AUTACs, ATTECs). Building on this foundation, we further explored how innovative approaches—such as linker arm engineering, expansion of E3 ligase resources, controllable responsive module design, and nanocarriers—drive optimization and breakthroughs in TPD selectivity, pharmacokinetics, and therapeutic breadth. Finally, integrating the latest clinical and frontier research, we conduct an in-depth analysis of TPD’s application prospects in major disease areas including cancer, neurodegenerative diseases, cardiovascular diseases, and infectious diseases. We also summarize and project key challenges in drug delivery, off-target effect control, and safety evaluation. Through this multidimensional review, we aim to reveal the strategic value of TPD technology in precision medicine and new drug development, providing insights and inspiration for its future direction.