NF-κB signaling in persistent high-risk cervical HPV infection: Clinical evidence, molecular mechanisms, and translational therapeutic opportunities.

Persistent infection with high-risk human papillomavirus (HPV) is the essential precursor to cervical carcinogenesis and remains a major global health challenge despite advances in vaccination and screening. While most cervical HPV infections are spontaneously cleared, a subset persists and progresses to cervical intraepithelial neoplasia (CIN) and ultimately invasive cervical cancer. Emerging evidence identifies nuclear factor kappa B (NF-κB) as a central regulator linking antiviral immunity, chronic inflammation, epithelial survival, and disease progression. In this hybrid review, we systematically synthesize clinical evidence regarding NF-κB activation in persistent cervical high-risk HPV infection and integrate mechanistic insights from molecular studies to develop a translational framework for therapeutic intervention. Current data suggest that HPV oncoproteins E6 and E7 selectively reprogram NF-κB signaling, attenuating antiviral interferon responses while maintaining inflammatory pathways that favor viral persistence and immune dysregulation. A stage-dependent model emerges in which early suppression of antiviral signaling is followed by chronic low-grade NF-κB activation, promoting epithelial survival, microenvironmental remodeling, and progression toward high-grade CIN. We further discuss pathway-specific therapeutic opportunities, including selective NF-κB modulation and integration with therapeutic E6/E7 vaccination. Collectively, NF-κB represents a promising biomarker and therapeutic target for host-directed strategies aimed at viral clearance and prevention of cervical cancer progression.