Musculoskeletal disorders: does cuproptosis hold the key?

Cuproptosis, a recently identified form of programmed cell death, is triggered by intracellular copper accumulation and executed through mitochondrial metabolic interference and proteostasis disruption. While emerging evidence has elucidated its pathophysiological roles in oncology, neurodegenerative disorders, and metabolic diseases, its mechanistic involvement and therapeutic potential in musculoskeletal disorders-including osteoarthritis, rheumatoid arthritis, osteoporosis, intervertebral disc degeneration, ankylosing spondylitis, bone tumors, skeletal muscle atrophy, and osteonecrosis of the femoral head (ONFH)-remain largely unexplored. This comprehensive review synthesizes current knowledge on the molecular mechanisms underlying cuproptosis in musculoskeletal pathophysiology, its potential as a disease-modifying factor, and the translational challenges that must be addressed before its clinical application. Furthermore, we highlight critical knowledge gaps and propose novel research directions that may help advance this emerging field.