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

Khantham, C.; Rodriguez-Martin, I.; Kerick, M.; Villanueva-Martin, G.; Callejas, J. L.; Ortego-Centeno, N.; Guillen-Del-Castillo, A.; Simeon-Aznar, C. P.; Ruiz-Villaverde, R.; Andres-Leon, E.; Martin, J.; Acosta-Herrera, M.

doi:10.64898/2026.05.06.723148

bioRxiv · 10.64898/2026.05.06.723148

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

Khantham, C.·Rodriguez-Martin, I.·Kerick, M.·Villanueva-Martin, G.·Callejas, J. L.·Ortego-Centeno, N.·Guillen-Del-Castillo, A.·Simeon-Aznar, C. P.·Ruiz-Villaverde, R.·Andres-Leon, E.·Martin, J.·Acosta-Herrera, M.

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Abstract

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, mechanotransduction, and MYC-associated stress programs. We further reveal that the fibrotic lesional environment shows sex differences: SFRP2DPP4 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.

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Khantham, C., Rodriguez-Martin, I., Kerick, M., Villanueva-Martin, G., Callejas, J. L., Ortego-Centeno, N., Guillen-Del-Castillo, A., Simeon-Aznar, C. P., Ruiz-Villaverde, R., Andres-Leon, E., Martin, J., Acosta-Herrera, M.. 2026-05-09. Sex-biased Fibroblast Subpopulations and Transcriptional Programs Reveal Mechanisms of Skin Lesion Development in Systemic Sclerosis. https://doi.org/10.64898/2026.05.06.723148

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