Abstract
Vulvar diseases are a neglected area of women's health, profoundly affecting patients' QOL. Lichen sclerosus is a chronic inflammatory vulvar skin disorder leading to severe itching, pain, scarring, and an increased risk of malignancy. Despite this burden, the molecular pathogenesis of vulvar lichen sclerosus is not well-understood, limiting treatment options. In this study, we analyze lesional, nonlesional, and healthy vulvar skin using technologies including spatial and single-cell transcriptomics. Our findings identify unifying molecular changes across multiple cell types in lesional vulvar lichen sclerosus skin, including keratinocyte stress response, necroptosis, and basal/stem cell depletion. Chronic T-cell activation, enhanced cytotoxicity, aberrant cell-cell communication, and elevated IFN-γ/JAK/signal transducer and activator of transcription signaling were also observed. Functional studies suggest keratinocytes' dual role as both targets of microenvironmental signaling (eg, IFN-γ) and sources of inflammatory alarmins (eg, S100A8/9). This work reveals keratinocytes as central players in vulvar lichen sclerosus pathogenesis and identifies potential biomarkers and therapeutic targets for future research.