Xiang Ziyang, Mei Huiling, Wang Honglin, Yao Xiaoyue, Rao Ji, Zhang Wentao, Xu Aoshuang, Lu Lin
Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Cell Dev Biol. 2025 Apr 11;13:1570131. doi: 10.3389/fcell.2025.1570131. eCollection 2025.
Cuproptosis, a recently identified form of copper-dependent cell death, arises from intracellular copper dyshomeostasis. As an essential trace element, copper plays a critical role in bioenergetic metabolism, redox regulation, and synaptic transmission. However, excessive copper exerts cytotoxic effects through multiple pathways, including increased reactive oxygen species (ROS) production, apoptotic cascade activation, necrotic membrane rupture, inflammatory responses, and mitochondrial dysfunction. Distinct from other cell death mechanisms, cuproptosis is characterized by copper ion binding to acetylated mitochondrial respiratory chain proteins, leading to pathogenic protein aggregation, iron-sulfur cluster depletion, and cellular collapse. Emerging evidence underscores aberrant copper accumulation and resultant proteotoxic stress as pivotal contributors to the pathogenesis of multiple musculoskeletal pathologies, including osteoporosis, osteoarthritis, sarcopenia, osteosarcoma, intervertebral disc degeneration, spinal cord injury, and biofilm-associated orthopedic infections. Understanding the spatiotemporal regulation of cuproptosis may provide novel opportunities for advancing diagnostic and therapeutic approaches in orthopedic medicine. This review synthesizes current insights into the molecular mechanisms of cuproptosis, its pathogenic role in musculoskeletal diseases, and the potential for biomarker-driven therapeutic interventions.
铜死亡是一种最近发现的铜依赖性细胞死亡形式，源于细胞内铜稳态失衡。作为一种必需的微量元素，铜在生物能量代谢、氧化还原调节和突触传递中起着关键作用。然而，过量的铜通过多种途径发挥细胞毒性作用，包括增加活性氧（ROS）生成、激活凋亡级联反应、坏死性膜破裂、炎症反应和线粒体功能障碍。与其他细胞死亡机制不同，铜死亡的特征是铜离子与乙酰化的线粒体呼吸链蛋白结合，导致致病性蛋白质聚集、铁硫簇耗竭和细胞崩溃。新出现的证据强调，异常的铜积累和由此产生的蛋白毒性应激是多种肌肉骨骼疾病发病机制的关键因素，包括骨质疏松症、骨关节炎、肌肉减少症、骨肉瘤、椎间盘退变、脊髓损伤和生物膜相关的骨科感染。了解铜死亡的时空调节可能为推进骨科医学的诊断和治疗方法提供新的机会。本综述综合了目前对铜死亡分子机制、其在肌肉骨骼疾病中的致病作用以及生物标志物驱动的治疗干预潜力的见解。
