Metabolomics of HPV Infection and Cervical Carcinogenesis: A Systematic Review of Human Studies

Infection with high-risk Human papillomavirus (HR-HPV), is the main etiological factor in the development of cervical cancer (CC), but the complex and interconnected molecular mechanisms driving its progression remain incompletely understood. In this context, metabolomics has emerged as a powerful tool for the identification of disease-specific metabolic alterations and the discovery of potential diagnostic and prognostic biomarkers. This systematic review compiles and analyzes findings from 17 human-based metabolomics studies on HPV infection, covering various stages of cervical disease, ranging from asymptomatic infection to low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) and invasive cervical cancer (ICC). Mass spectrometry (MS) approaches have revealed key metabolites and altered pathways involving amino acid, lipid, and energy metabolism. Notably, several high-performing biomarkers (AUC > 0.9) have been identified in non-invasive samples such as cervical mucus and urine, highlighting their clinical potential. Moreover, recent integrative multi-omics studies incorporating metagenomic data have revealed a critical interplay between HPV, host metabolism, and the cervicovaginal microbiota, in which Lactobacillus depletion and microbial dysbiosis contribute to inflammation and oxidative stress, thereby promoting HPV persistence and disease progression. These findings support the inclusion of metabolomics in early diagnostic screening and suggest new therapeutic strategies targeting redox balance, lipid biosynthesis, and amino acid pathways. Future research should aim to validate these biomarkers in larger cohorts and explore microbiota-modulating interventions as potential preventive strategies.