Multi-omics analysis unveiled fibroblast-mediated pathogenesis in male genital lichen sclerosus

Male genital lichen sclerosus (LS), a chronic inflammatory dermatological condition, has been recognized for its profound implications on the quality of life among males. The exact etiological factors behind this prevalent condition remained largely enigmatic. In this research, we employed a multi-omics strategy to identify and elucidate the underlying histological biomarkers and the fundamental pathogenesis associated with male genital LS. A comprehensive cell atlas of male genital LS disease was constructed, highlighting a pronounced increase in T cells and a remarkable reduction in keratinocytes within the male genital LS samples. Further insights elucidated the enhanced crosstalk between fibroblasts and T cells via the collagen-CD44 axis, and between fibroblasts and keratinocytes through the APP-CD74 signaling pathway. This molecular dialogue was implicated in the immune infiltration and hyperkeratosis observed in the dermal-epidermal layer of male genital LS. Subsequently, we integrated single-cell RNA sequencing data with genome-wide association study findings to explore the cell-type-specific genes predisposing to the development of male genital LS. The analysis underscored the pivotal role of GAS1, which was enriched in fibroblasts and implicated in the pathogenesis of male genital LS progression. Collectively, we highlighted the critical role of fibroblasts in initiating male genital LS onset, generating interactions with T cells and keratinocytes, and eliciting the classical histological features of male genital LS.