Hypoxia, cuproptosis, and osteoarthritis: Unraveling the molecular crosstalk

Aberrant changes in the hypoxic microenvironment are implicated in osteoarthritis (OA) development. Cuproptosis, a unique copper-dependent form of regulated cell death that depends on the activity of key enzymes in mitochondrial metabolism, is also linked to oxygen levels. However, the crosstalk among hypoxic environment, cuproptosis, and OA development remains unclear. This study confirmed that oxygen levels in the OA model gradually increased during OA progression, which suppressed the expression of anabolic genes for articular cartilage extracellular matrix, upregulated catabolic genes, and increased the cell death rate of primary chondrocytes. Mechanistically, oxygen elevation upregulated the expression of solute carrier family 31 member 1 (SCL31A1), a transmembrane pump facilitating copper uptake, whereas it downregulated the expression of ATPase copper transporting beta (ATP7B), a copper chaperone facilitating copper efflux, leading to aberrant copper accumulation in the cells. Ultimately, this accumulation efficiently induces oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), triggering cell death, known as cuproptosis. Hypoxia-inducible factor-1α (HIF-1α), induced under hypoxic conditions, is negatively correlated with DLAT and the severity of OA, as confirmed in human and rat cartilage. Furthermore, siRNA-mediated HIF-1α silencing sensitized primary chondrocytes to cuproptosis, whereas HIF-1α stabilization had protective effects. In summary, increased oxygen levels in the cartilage induce cuproptosis, thereby accelerating OA progression, whereas HIF-1α stabilization mitigates this process. These findings may provide novel therapeutic targets for OA treatment in clinical practice.