Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism.

Copper, predominantly present in bones, plays a crucial role in bone formation. However, when copper homeostasis is disrupted, excessive copper can trigger harmful inflammation and a novel form of cell death known as cuproptosis. The impact of cuproptosis on bone metabolism remains unclear. In this study, we demonstrated that excessive copper acts as an aggravator in osteoclastogenesis and bone resorption. We observed that the expression levels of the copper importer SLC31A1 and dihydrolipoamide S-acetyltransferase (DLAT) were positively correlated with bone loss in both human chronic apical periodontitis (CAP) tissues and mouse CAP models. Untargeted metabolomics analysis and screening of glucose metabolism enzymes revealed that glycogen synthesis was inhibited during cuproptosis. Mechanistically, excessive copper hindered glycogen synthesis via glycogen synthase 1 (GYS1), which limited the availability of glycogenolysis-derived glucose-6-phosphate (G6P) flux into pentose phosphate pathway (PPP), and was unable to yield abundant NADPH to ensure high demand of glutathione (GSH) for macrophage survival. The inhibition of glycogen synthesis intensified cuproptosis and bone-resorption activity. Moreover, excessive copper bound to H3K27me3, which further epigenetically inhibited the gene transcription of GYS1, thereby affecting glycogen synthesis and exacerbating cuproptosis and bone resorption. Furthermore, the disruption of glycogen metabolism intensified cuproptosis and promoted inflammatory bone loss in vivo. Our finding highlighted the complex interplay among copper homeostasis, glycogen metabolism, and the osteo-immune system, suggesting new therapeutic strategies for managing inflammatory bone diseases and other copper accumulation-related conditions through the metabolic reprogramming of cells.