Persistent detection of high risk human papillomavirus (HPV) is required for cervical carcinogenesis, yet the metabolic phenotype associated with distinct HPV transition states remains incompletely defined. We analyzed vaginal metabolomics data from 71 HIV negative, nonsmoking, premenopausal women without other sexually transmitted infections, grouped by three visit HPV trajectories: persistent negative (NNN, n=20), late incident positivity (NNP, n=9), conversion with persistence (NPP, n=13), clearance after prior positivity (PPN, n=16), and persistent positive (PPP, n=13). After detection based filtering, 186 putative and 64 quantitatively estimated metabolites were retained for integrated univariate, multivariate, network, pathway, and machine learning analyses. Global class separation was weak by PERMANOVA and by five class classification, indicating that the vaginal metabolome does not reorganize broadly across all HPV states. In contrast, trajectory specific signals were reproducible. The strongest pairwise contrast was NNP versus PPP (best cross validated ROC AUC 0.778; permutation p=0.039). Glycolic acid was the dominant single metabolite, particularly for NNP versus PPP (Mann Whitney p=0.000696, FDR=0.0446, AUROC=0.902; detection 88.9% versus 15.4%; combined abundance+detection FDR=0.0010). Persistent positivity was characterized by a focused uracil high, methyl donor/redox low signature, including lower glycolic acid, S adenosylmethionine, NAD+, and betaine, together with higher uracil. Ratio mining further sharpened discrimination, with uracil/S adenosylmethionine and uracil/creatinine among the best PPP classifiers, and glucose 1 phosphate/isovaleric acid valeric acid strongly separating NNP from NPP. These data support a model in which HPV trajectory is encoded by targeted metabolic states rather than a diffuse HPV positive versus HPV negative metabolomic shift.

The authors have declared no competing interest.

The project described was supported by the African Collaborative Center for Microbiome and Genomics Research grants (NHGRI/NIH U54HG006947) from the NIH Office of the Director/NHGRI, Maryland Department of Health Cigarette Restitution Fund Program (grant number CH-649-CRF), and the University of Maryland Greenebaum Comprehensive Cancer Center Support Grant (National Cancer Institute Award Number: P30CA134274). The funding agencies did not play any role in data collection, analysis, or publication

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Ethical approval was obtained from the National Health Research Ethics Committee of Nigeria (NHREC/01/01/2007-26/10/2025I) and the institutional ethics committees at the University of Maryland School of Medicine, Baltimore (US) (IRB Number HP-00058830). All participants gave written informed consent in accordance with the Declaration of Helsinki and the Nigerian National Code for Health Research Ethics

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