Lipid reprogramming of stratified squamous epithelium by the high-risk HPV E6 and E6/E7 oncoproteins

High risk human papillomavirus (HPV) infection and genome integration with pronounced expression of the viral E6/E7 oncogenes is the major cause of cervical cancer. Emerging evidence suggests that HPV reprograms host metabolism to support viral persistence and cellular transformation. However, global HPV oncogene-induced lipidomic reprogramming remains poorly understood, particularly at early stages of HPV-induced transformation.

We sought to define the regulation of lipid metabolism in squamous epithelia of transgenic mice expressing the HPV16 oncogene E6 alone or in conjunction with E7.

Untargeted lipidomics was used to identify novel lipid biomarkers in the skin and female reproductive tract (FRT) of HPV16 E6 and E6/E7 transgenic compared to wild-type (WT) mice. To investigate enzymatic dysregulation of lipids by HPV oncogene expression, we employed Lipid Network Explorer (LINEX²), which analyzes lipidomics data through lipid enrichment analysis. We also used the Global Natural Product Social Molecular Networking (GNPS) platform to enhance lipid identification, exploring molecular networking to improve feature annotation.

Our lipidomic analysis produced several new observations. First, E6 expression caused a consistent alteration of glycerophospholipids, with particularly significant substrate-product shifts in the phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) pathway in the skin. Second, E6/E7 expression caused a dysregulation of glucosylceramide (GlcCer) biosynthesis. Third, both E6/E7 expressing skin and FRT tissues exhibited a redox imbalance and increased levels of oxidized lipids, including oxylipins and several oxidized PCs. These findings suggest that HPV oncoproteins drive lipid reprogramming, potentially contributing to early HPV-related tumorigenesis.

These findings provide new insights into HPV‑induced lipid reprogramming and establish a framework for future studies examining the functional and clinical relevance of lipid alterations in HPV‑associated cancers.