Research advances of copper homeostasis and cuproptosis in orthopedic diseases

Abstract Copper is an essential trace element that plays a significant role in human physiological functions. However, abnormal accumulation of copper can trigger a programmed cell death mechanism known as cuproptosis, which has a significant pathological impact, especially in orthopedic diseases such as osteoarthritis (OA), rheumatoid arthritis (RA), osteosarcoma (OS), and osteoporosis (OP). Cuproptosis not only causes damage to cell membranes, proteins and DNA through oxidative stress mechanisms, but also triggers apoptosis by disrupting mitochondrial function, thereby further exacerbating the structural damage of bone and cartilage tissues. The cuproptosis-related genes (CRGs) exhibit unique biological functions in regulating these pathological processes, and thus become potential diagnostic markers and therapeutic targets. In this regard, we have proposed an innovative therapeutic approach that utilizes the water gel sustained-release technology to load natural antioxidants. The aim is to achieve multi-dimensional targeted cuproptosis through improving drug delivery. Furthermore, natural substances such as sage extract, cinnamon and probiotics have demonstrated the potential for potent antioxidant and anti-inflammatory effects, providing a foundation for future therapeutic strategies. A key challenge for these strategies will be to precisely modulate copper levels to induce therapeutic cuproptosis in pathological cells (e.g., in osteosarcoma or hyperactive osteoclasts) while preserving the essential physiological functions of copper in normal bone and cartilage remodeling. Exosomal miRNAs provide a new perspective for intervening in the pathologies caused by copper through regulating copper homeostasis and related signaling pathways. Future research will focus on optimizing the combination application of these natural drugs, exploring the potential of different copper chelators and pioneering the design of innovative biomaterials, in order to achieve better control of cuproptosis and innovative progress in the treatment of orthopedic diseases.