The role of cuproptosis in osteoporosis: Molecular mechanisms and cell-specific regulation in bone metabolic imbalance.

The pathogenic mechanisms of osteoporosis (OP), a systemic metabolic bone disease marked by an imbalance between bone growth and resorption, are still not fully understood.Through the specific binding of copper ions to mitochondrial the tricarboxylic acid (TCA) cycle acyl-CoA deoxygenases (like DLAT and PDHA1), cuproptosis-a novel copper-dependent form of programmed cell death-causes protein toxicity stress, protein aggregation, and iron-sulfur cluster (Fe-S cluster) depletion. This finding provides a fresh viewpoint on how to explain the molecular processes underlying oxidative stress.This study offers a comprehensive analysis of the fundamental molecular processes behind cuproptosis, with an emphasis on how it is regulated specifically in bone metabolism. These mechanisms include the regulation of copper homeostasis, FDX1-mediated lipoylation modification, and Fe-S cluster metabolic disturbance. We hypothesize that the RUNX2-PDHA1 axis may underlie the high mitochondrial respiration dependence and enhanced lipoylase expression that could render osteoblasts sensitive to cuproptosis, while osteoclasts are naturally resistant due to their reliance on glycolysis and the RANKL-ERK1/2 pathway-mediated inhibition of lipoylation.Furthermore, genes linked to cuproptosis (PDHA1, FDX1, and CDKN2A) control metabolic reprogramming, the linkage between oxidative stress and inflammation, and cellular senescence, all of which contribute to the development of OP. An additional factor contributing to bone metabolic imbalance is the cuproptosis-dependent control of T-cell cytokine production and macrophage polarization in the bone immunological milieu. According to a theoretical framework for creating focused therapeutic techniques, copper-induced death contributes to OP disease through a cascade process that includes "copper metabolism abnormalities - cell-specific differential death - immune microenvironment disruption."