Cutaneous papillomaviruses infection rewires fatty-acid metabolism.

BACKGROUND: Cutaneous warts are common HPV-induced lesions with limited treatments for recalcitrant cases. Fatty-acid metabolism (FAM) maintains epidermal homeostasis, but whether papillomavirus infection actively suppresses FAM programs and whether restoring FAM-related regulators can modulate keratinocyte dysfunction remain unclear. METHODS: We established a murine MmuPV1 wart model and performed bulk RNA-seq. FAM-related DEGs were identified via network analysis and machine learning. Immune infiltration was assessed by CIBERSORT. In vitro validation used HPV16 E6/E7-transfected HaCaT cells. RESULTS: Transcriptome analysis revealed significant suppression of FAM pathways in wart lesions. Four key FAM-related differentially expressed genes (Nr1h3, Dgat1, Scd1, and Fabp4) were identified from RNA-seq-based bioinformatic analyses and further supported by in vitro E6/E7-related expression assays. In vitro, HPV16 E6/E7 expression reduced these genes in HaCaT keratinocytes. NR1H3 overexpression partially attenuated E6/E7-induced proliferation and differentiation abnormalities, lipid-droplet accumulation, and IL-6/CCL2 secretion, with partial restoration of ABCA1 expression and inhibition of NF-kB activation. CONCLUSIONS: Papillomavirus infection is associated with coordinated suppression of FAM-related programs. NR1H3, Dgat1, Scd1, and Fabp4 represent candidate metabolic regulatory nodes; their therapeutic relevance requires further in vivo validation.