Downregulation of O‐ <scp>GlcNAcylation</scp> enhances etoposide‐induced p53‐mediated apoptosis in <scp>HepG2</scp> human liver cancer cells

Etoposide, an anticancer drug that inhibits topoisomerase II, is commonly used in combination chemotherapy. However, the impact of O-GlcNAcylation regulation on etoposide's anticancer effects has rarely been investigated. This study evaluated the effect of etoposide on cellular O-GlcNAcylation and whether modulating this process enhances etoposide-induced apoptosis. O-GlcNAc expression was measured after 24 h of etoposide treatment, and the effect of O-GlcNAc transferase (OGT) inhibition by OSMI-1 on etoposide's anticancer activity in HepG2 human liver cancer cells was quantitatively analyzed. Additionally, molecular analyses were used to confirm that the observed effects were mediated by p53-induced apoptosis. Etoposide reduced O-GlcNAcylation in a dose-dependent manner without directly interacting with OGT. Cotreatment with 20 μm of OSMI-1 lowered the IC₅₀ value for cell viability by approximately 1.64-fold to 60.68 μm and increased the EC₅₀ value for cytotoxicity by around 4.07-fold to 43.41 μm. Furthermore, this synergistic effect was linked to the activation of the p53/caspase-3/PARP1 pathway. These findings suggest that downregulating O-GlcNAcylation may enhance the efficacy of etoposide-based chemotherapy and help overcome tumor resistance.