Sex-Specific Transcriptomic Profiles in Psoriatic Lesions: A Large-Scale Integrative Study

Psoriasis, a chronic inflammatory skin disease affecting men and women equally, presents distinct gender-based differences in severity and treatment response. While molecular mechanisms underlying psoriasis are well-studied, sex-specific differences remain largely unexplored. To address this, we conducted a comprehensive analysis of transcriptomic data from lesional psoriasis skin and healthy controls, comparing male and female cohorts. Our findings reveal 2760 overlapping differentially expressed genes (DEGs) between sexes, highlighting shared pathways like IL-17 signaling and Th17 differentiation. However, sex-specific pathways emerged, including male-enriched PI3K-Akt signaling and chemokine receptor activity, and female-enriched glycolysis and AHR-NRF2 pathways. Upstream regulator analysis identified sex-specific drivers, including VEGFA activation and CFTR inhibition in males, and AHR activation and FGF21 inhibition in females. Notably, Regulatory T cells (Tregs) and neutrophil abundance differed by sex, aligning with disease severity trends. These results highlight sex-associated molecular and cellular disparities that may be relevant to understanding differences in disease manifestation and treatment response. As an exploratory, hypothesis-generating transcriptomic analysis, this study lays the groundwork for future experimental and clinical validation of sex-specific mechanisms in psoriasis.