Cuproptosis in age-related orthopedic diseases: mechanisms and therapeutic prospects.

Cuproptosis is an emerging copper-dependent and mitochondria-associated form of regulated cell death (RCD) that links intracellular labile copper accumulation to metabolic vulnerability. Mechanistically, cuproptosis is triggered by intracellular copper accumulation, leading to aggregation of lipoylated tricarboxylic acid (TCA) cycle proteins, destabilization of iron-sulfur cluster proteins, and proteotoxic stress-induced bioenergetic collapse. Aging-associated orthopedic disorders-including osteoarthritis (OA), osteoporosis (OP) and intervertebral disc degeneration (IVDD)-represent a rapidly expanding global burden and share convergent pathological features such as mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and progressive skeletal cell loss. However, the upstream regulatory networks integrating these hallmarks remain incompletely defined. Aging may be accompanied by systemic copper redistribution, impaired intracellular copper buffering, expansion of labile copper pools in vulnerable cellular microenvironments, and concomitant iron dysregulation. Together, these alterations form an interconnected metal-redox-metabolic axis that sensitizes skeletal tissues to degenerative remodeling. In this review, we synthesize current advances in copper homeostasis and the molecular determinants of cuproptosis, with particular emphasis on their potential involvement in OA, OP, and IVDD. We further distinguish established evidence from mechanistic hypotheses and discuss why serum copper, tissue copper, and intracellular labile copper should not be interpreted interchangeably. Finally, we outline future perspectives on targeting cuproptosis for the treatment of age-related orthopedic diseases, aiming to stimulate further clinical investigation and therapeutic innovation.