Spatial and Single-Cell Transcriptomics Reveal Keratinocytes as Key Players in Vulvar Lichen Sclerosus Pathogenesis.

Area of Science:

• Dermatology
• Immunology
• Molecular Biology

Background:

• Vulvar diseases, including lichen sclerosus (LS), significantly impact women's quality of life.
• Vulvar lichen sclerosus (VLS) is a chronic inflammatory condition with poorly understood molecular pathogenesis, hindering effective treatments.
• VLS is associated with severe symptoms and an increased risk of vulvar malignancy.

Purpose of the Study:

• To elucidate the molecular pathogenesis of vulvar lichen sclerosus (VLS).
• To identify molecular changes and cellular mechanisms underlying VLS.
• To discover potential biomarkers and therapeutic targets for VLS.

Main Methods:

• Comparative analysis of lesional, non-lesional, and healthy vulvar skin.
• Application of spatial and single-cell transcriptomics.
• Functional studies investigating cellular roles and signaling pathways.

Main Results:

• Identified unifying molecular changes in lesional VLS skin, including keratinocyte stress, necroptosis, and stem cell depletion.
• Observed chronic T cell activation, increased cytotoxicity, altered cell communication, and elevated IFN-γ/JAK/STAT signaling.
• Demonstrated keratinocytes act as both targets of inflammatory signals and sources of alarmins.

Conclusions:

• Keratinocytes play a central role in the pathogenesis of VLS.
• The findings provide insights into the complex interplay of immune and epithelial cells in VLS.
• Identified potential diagnostic biomarkers and therapeutic targets for VLS management.