Sex-biased Fibroblast Subpopulations and Transcriptional Programs Reveal Mechanisms of Skin Lesion Development in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with pronounced sex differences: females are more frequently affected and males develop more severe skin fibrosis. The cellular mechanisms of this disparity remain unclear. Here we use single-cell transcriptomics of lesional, non-lesional, and healthy skin to define fibroblast states and sex-biased transcriptional programs during lesion development. We identify a sex-dependent divergence in SSc fibrotic regulation. Female fibroblasts exhibit heightened inflammatory signaling and canonical TGF-{beta}-driven extracellular matrix production, whereas male fibroblasts preferentially engage non-canonical TGF-{beta} pathways, mecha