Latest ArticlesTargeted protein degradation (TPD) technology achieves selective degradation of target proteins through the ubiquitin-proteasome system (UPS) or lysosomal pathways. Among TPD strategies, proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach in innovative drug discovery, offering unique advantages such as the ability to target "undruggable" proteins, catalytic degradation kinetics, potential to circumvent drug resistance, and high selectivity. However, conventional small-molecule PROTACs depend on ligands binding to target proteins, limiting their effectiveness against molecules without well-defined binding sites, such as transcription factors (TFs) and RNA-binding proteins (RBPs). To overcome this limitation, oligonucleotide-based PROTAC technology has been developed, utilizing sequence-specific nucleic acid recognition to significantly expand the repertoire of degradable targets. This review systematically summarizes recent advances in oligonucleotide-PROTACs, including innovative designs like TF-PROTACs, RNA-PROTACs, G4-PROTACs, and aptamer-PROTACs, along with their therapeutic potentials. We further discuss persisting challenges such as molecular stability and delivery efficiency, and propose future directions for the field. By integrating nucleic acid molecular biology with protein degradation technologies, this interdisciplinary paradigm promises to unlock novel therapeutic strategies for "undruggable" targets and previously intractable diseases.
Breast cancer remains one of the most prevalent malignancies worldwide, with approximately 2.3 million new cases and 670 000 deaths reported globally in 2022. Current therapeutic challenges include the difficulty in targeting breast cancer-associated proteins lacking active sites through traditional small-molecule inhibitors, as well as the high incidence of acquired drug resistance, which collectively undermine treatment outcomes. The advent of proteolysis-targeting chimera (PROTAC) technology has provided a solution, offering a unique protein degradation mechanism to circumvent these limitations. Nevertheless, clinical translation of PROTACs requires addressing inherent limitations such as poor solubility, low bioavailability, and insufficient targeting specificity. To overcome these barriers, multifunctional nano-delivery systems have emerged as a promising technological platform to enhance the therapeutic potential of PROTACs. This review systematically examines the latest advances in nanotechnology-enabled PROTAC delivery for breast cancer treatment, with particular emphasizes rational nanocarrier design principles and synergistic mechanisms of antitumor combination therapies. We further critically analyze persistent translational challenges and propose forward-looking solutions. The integration of nanotechnology with PROTACs not only overcomes the limitations of traditional therapies but also offers new insights into the precise treatment of breast cancer.
Targeted protein degradation (TPD) drugs, which specifically degrade protein of interest, provide novel therapeutic strategies for a spectrum of diseases. However, traditional small-molecule degraders still face challenges such as poor bioavailability, limited availability of E3 ligases, and significant off-target effects. Macromolecule-based TPD agents, characterized by greater design flexibility and enhanced specificity, hold promise for overcoming the limitations of conventional proteolysis-targeting chimeras (PROTACs). This article focuses on macromolecular degradation systems, systematically analyzing and comparing the molecular mechanisms, clinical translation potential, and inherent challenges of different technological approaches based on two major intracellular degradation pathways—the ubiquitin-proteasome system and the lysosomal pathway. Furthermore, we discussed emerging directions, including transmembrane protein degradation and light-controlled protein degradation, offering insights for developing precision-targeted protein degradation-based therapeutic frameworks.
The development of therapeutic interventions for central nervous system (CNS) diseases poses significant challenges. These challenges are primarily attributable to the limitations imposed by the blood-brain barrier (BBB) permeability and the inherent complexity of protein aggregates. Targeted protein degradation (TPD) technology selectively removes pathogenic proteins through the ubiquitin-proteasome system or lysosomal pathways, offering a new strategy for CNS treatment. In comparison with conventional small molecule drugs, TPD employs an event-driven mode of action, capable of degrading β-amyloid and other "undruggable" targets, and demonstrating efficacy at sub-chemometric doses. This is anticipated to markedly reduce the complexity of CNS delivery. The disconnecting of pharmacodynamics and pharmacokinetics further reduces the risk of off-targeting, making it particularly suitable for the CNS, a therapeutic area that requires a high degree of drug safety. Three CNS degraders have already entered clinical trials. This review comprehensively elaborates on the application progress of TPD technologies based on different degradation systems in the treatment of CNS diseases, systematically analyzes the advantages and limitations of each technology, and discusses the common challenges and general optimization strategies for TPD application in CNS disease therapy. The findings aim to provide new insights for the in-depth application of TPD technology in the treatment of CNS diseases.
Neurodegenerative diseases (NDDs) are marked by disruptions in protein homeostasis, including abnormal synthesis, misfolding, aggregation, and defective degradation of pathogenic proteins, leading to neurotoxicity. In recent years, multilayered therapeutic strategies targeting protein homeostasis have been developed, such as transcriptional and translational regulation, conformational stabilization, aggregation inhibition, and protein clearance approaches represented by targeted protein degradation (TPD). Since the pathological lesions of NDDs are primarily located in the central nervous system, effective interventions require that therapeutic agents cross the blood-brain barrier (BBB) and be precisely delivered to diseased brain regions. This review systematically summarizes the pathogenic mechanisms underlying protein homeostasis imbalance in NDDs and highlights current therapeutic strategies, with an emphasis on recent advances and therapeutic potential of TPD approaches. We further overview various brain-targeted nanodelivery systems, including those responsive to the brain microenvironment and capable of targeting specific cells and subcellular organelles, which collectively enable precise trans-BBB delivery and intracellular targeting. These advances support the development of precision therapies aimed at restoring protein homeostasis. This review provides insights into the progress of brain-targeted TPD technologies and their supporting nanodelivery strategies.
Molecular glues can modulate biological functions by specifically inducing interactions between target proteins and E3 ubiquitin ligases, demonstrating significant advantages for disease treatment. However, the discovery of most molecular glues still relies on serendipity, lacking systematic methods and rational design strategies. In recent years, rapid advances in chemical biology and in-depth research on molecular glue-protein interaction mechanisms have gradually enabled systematic development of molecular glues. Therefore, this review aims to organize discovery strategies and representative molecules from three perspectives: serendipitous discovery, screening methods, and rational design, providing critical insights and references for future molecular glue development.
Proteostasis is a core biological process through which cells maintain the stability and functional integrity of the proteome via a multi-level quality control network. As a key molecule in the ubiquitination regulatory pathway, the deubiquitinase USP7 can drive tumorigenesis and progression by altering the ubiquitination status of substrate proteins when its expression is aberrant or activity is dysregulated, thus emerging as a critical target in precision cancer therapy. This article systematically outlines the structural features of USP7, its role in regulating substrate protein homeostasis, and its biological functions in tumor development. It focuses on recent advances in USP7-based anti-tumor strategies, including the development of small-molecule inhibitors, applications of proteolysis-targeting chimeras (PROTACs) technology, and exploration of novel approaches such as deubiquitinase-targeting chimeras (DUBTACs). This review provides a systematic theoretical framework and cutting-edge research directions for the development of USP7-targeted anti-tumor drugs.
Traditional Chinese medicines (TCMs), with its rich historical legacy and demonstrated efficacy in treating chronic non-communicable diseases, particularly in addressing cancer, cardiovascular diseases, diabetes, and chronic respiratory diseases, presents unique challenges for scientific investigation due to its complex chemical composition and poorly understood mechanisms of action. This review systematically examines the evolution of target fishing technology, evaluates established target identification technology and ligand fishing technology in TCMs research, and synthesizes recent advancements in applying these methodologies to elucidate the therapeutic mechanisms of TCMs for major chronic diseases, with special emphasis on component-target interactions. By providing a critical analysis of current applications and future directions, this work aims to advance the integration of target fishing technologies into modern TCMs research and establish a robust framework for mechanistic studies in this field.
Alzheimer's disease (AD) is a complex neurodegenerative disorder, and its pathological mechanisms are not yet fully understood. In recent years, mitochondrial dysfunction has been recognized as one of the important pathological features of AD. As the central hub of intracellular energy metabolism, mitochondria maintain ATP homeostasis through the tricarboxylic acid cycle and oxidative phosphorylation under physiological conditions, and they are involved in important physiological processes. However, under the pathological state of AD, mitochondrial function undergoes statistically significant changes, characterized by bioenergetic metabolism imbalance, impaired mitophagy, abnormal dynamics (including excessive fission and fusion defects), and excessive production of mitochondrial reactive oxygen species. Moreover, abnormal interactions between mitochondria and the endoplasmic reticulum disrupt cellular homeostasis, thereby significantly accelerating neuronal degeneration by exacerbating the pathological processes of AD. This article systematically reviews the core pathological features of AD, focusing on the physiological functions of mitochondria and their dynamic changes during the pathological progression of AD. Finally, this article summarizes the anti-AD therapeutic strategies that regulate mitochondrial function, including small molecule drugs and natural products, providing new ideas and potential solutions for the treatment of AD.
Neuroinflammation plays a pivotal regulatory role in the onset and progression of various central nervous system diseases. As a key immune sensor, the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, upon activation, can exacerbate neuroinflammation, leading to neuronal injury and death, thereby accelerating the pathological processes of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Consequently, the NLRP3 inflammasome has emerged as an important therapeutic target for modulating neuroinflammation. In recent years, significant progress has been made in the development of NLRP3 inflammasome inhibitors. Numerous novel inhibitors have been identified that effectively reduce inflammatory responses and protect neurons from damage, demonstrating promising efficacy in animal models, particularly in improving cognitive and motor functions. This review will summarize the canonical activation mechanisms of the NLRP3 inflammasome, explore its pathogenic roles in central nervous system diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and depression, and provide an overview of recent advances in NLRP3-targeted drug development, aiming to offer new insights and strategies for the treatment of central nervous system diseases.
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