Cuproptosis and its potential role in Musculoskeletal Disease

Ziyang Xiang ¹ Huiling Mei ² Honglin Wang ¹ Xiaoyue Yao ¹ Ji Rao ¹ Wentao Zhang ¹ Aoshuang Xu ^3* Lin Lu ^1*

• ¹ Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
• ² Department of Rheumatology and Immunology, Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, wuhan, China
• ³ Institute of Hematology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

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. Keyword ： Cuproptosis, osteoporosis, osteoarthritis, osteosarcoma, intervertebral disc degeneration, spinal cord injury, and osteomyelitis 1. Introduction Copper is an indispensable trace metal element in biological systems, extensively involved in critical physiological processes including energy metabolism, antioxidant defense, and connective tissue formation(L. Chen, Min, & Wang, 2022; Tian, Jiang, Zhou, & Zhang, 2023). As a cofactor for metalloenzymes such as cytochrome C oxidase (COX), superoxide dismutase (SOD), and lysyl oxidase (LOX), copper plays pivotal roles in maintaining mitochondrial respiratory chain function, scavenging free radicals, and promoting collagen cross-linking, which are essential for skeletal development, joint stability, and muscular contractility(Z. Chen et al., 2024; Lutsenko, Roy, & Tsvetkov, 2025). However, the strong redox activity of copper endows it with dose-dependent dual effects at the cellular level: under physiological concentrations, copper supports normal cellular functions through precise homeostatic regulation networks, whereas excessive accumulation triggers irreversible cellular damage via reactive oxygen species (ROS) generation and direct proteotoxicity(Tang, Kroemer, &