Lineage-Specific Sex-Biased Transcriptional Programs in Healthy Human Truncal Skin Revealed by Single-Cell Transcriptomics

<b>Background/Objectives</b>: Sex differences influence skin physiology, immune regulation, and disease susceptibility, but the cellular organization of sex-biased transcriptional programs in healthy human skin remains incompletely defined. We aimed to define sex-associated differences in cellular composition and gene expression in healthy adult truncal skin at single-cell resolution. <b>Methods:</b> We constructed a sex-resolved single-cell transcriptomic atlas of healthy human truncal skin by integrating scRNA-seq data from 12 donors (5 males, 7 females). After quality control, 107,967 cells were classified into 14 major cell types. Sex-associated differences were assessed using donor-level pseudo-bulk analyses at both whole-skin and cell-type-resolved levels. <b>Results:</b> The cellular composition was conserved between sexes, with significant differences in mast cells and regulatory T cells. Whole-skin pseudo-bulk analysis identified distinct male-biased and female-biased transcriptional programs. Male-biased signals were linked to extracellular matrix organization and immune responses, while female-biased signals involved ion transport and neuromodulation. Cell-type-resolved analysis revealed that most sex-biased genes were lineage-specific, with minimal cross-lineage sharing. <b>Conclusions:</b> Sexual dimorphism in healthy human truncal skin is encoded through lineage-structured transcriptional regulation rather than broad compositional changes, providing a framework for understanding sex-biased skin homeostasis and disease susceptibility.