泛素蛋白酶体系统（UPS）致力于降解细胞内蛋白质以调节体内稳态和生物体功能。这些酶级联通过共价结合泛素分子来多样化地标记和修饰靶蛋白。在 UPS 中，E3 泛素连接酶是关键成分，具有识别蛋白质并将其呈递给蛋白酶体进行蛋白水解的优点。作为蛋白质稳态的主要调节因子，E3 连接酶对于不同系统中正常的细胞行为是不可或缺的，并且它们在生理性骨生长和骨代谢中得到了很好的描述。病理上，代谢性骨病、关节炎、骨肿瘤和肿瘤骨转移等经典的骨相关疾病也以UPS依赖性方式进行描述。因此，骨骼系统受到UPS的广泛调控，其底层机制值得总结。此外，基于目前的治疗现状，本综述阐述的正常或病理性成骨和肿瘤发生凸显了 UPS 研究的临床意义。作为一种可能弥补UPS治疗局限性的策略，对新兴的PROTAC进行了全面描述，以说明其在临床应用中的潜力。总而言之，本次综述的目的是为探索基于 UPS 的骨相关疾病新治疗策略提供更多证据。© 2023 中国药学会和中国医学科学院药物研究所。由 Elsevier B.V. 制作和主持

The ubiquitin-proteasome system (UPS) dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms. These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules. In the UPS, E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis. As the major regulators of protein homeostasis, E3 ligases are indispensable to proper cell manners in diverse systems, and they are well described in physiological bone growth and bone metabolism. Pathologically, classic bone-related diseases such as metabolic bone diseases, arthritis, bone neoplasms and bone metastasis of the tumor, etc., were also depicted in a UPS-dependent manner. Therefore, skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism. Furthermore, based on the current status of treatment, normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research. As a strategy possibly remedies the limitations of UPS treatment, emerging PROTAC was described comprehensively to illustrate its potential in clinical application. Altogether, the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.