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-β-driven extracellular matrix production, whereas male fibroblasts preferentially engage non-canonical TGF-β pathways, mechanotransduction, and MYC-associated stress programs. We further reveal that the fibrotic lesional environment shows sex differences: SFRP2⁺DPP4⁺ fibroblasts predominate in females and COL11A1⁺/COCH ⁺ in males. Our findings uncover cellular mechanisms underlying sex differences in SSc fibrosis, highlight opportunities for sex-informed therapeutic strategies and underscore the necessity of integrating biological sex into precision medicine frameworks to identify divergent molecular drivers of fibrotic disease.