HPV E6/E7, O-GlcNAcylation and mitochondrial remodeling in cervical cancer: mechanistic links and translational opportunities

Persistent high-risk human papillomavirus (HPV) infection initiates cervical carcinogenesis, while progression and treatment resistance also involve metabolic adaptation. O-GlcNAcylation is a reversible post-translational modification (PTM) controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), with UDP-GlcNAc generated by the hexosamine biosynthetic pathway (HBP) serving as the donor substrate. This review evaluates evidence linking HPV E6/E7-associated metabolic demand, HBP flux, O-GlcNAcylation, and mitochondrial function. We distinguish observations made under untreated conditions from acute treatment responses, identify whether validated resistant models were used, and examine HPV genotype as a source of heterogeneity. Cervical cancer studies support links between O-GlcNAcylation and pathways involved in growth and survival, but no mitochondrial O-GlcNAcylation site has been causally validated in HPV-positive cervical cancer. We therefore grade evidence by model, temporal context, and causal depth and place the proposed relationships within a broader PTM network. This synthesis separates findings obtained in cervical cancer from mechanisms inferred from other systems and identifies the main gaps limiting biomarker and therapeutic development.