Cell-specific genetic effects of topical glucocorticoids in human skin

Summary: Abstract Body: Topical glucocorticoids (GCs) are among the most prescribed medications in dermatology, serving as first-line treatments for many inflammatory skin conditions. Despite their widespread use, GCs exhibit variable effects: while they effectively suppress inflammation, they can also lead to resistance, adverse effects such as skin atrophy, and paradoxical exacerbation of inflammation. The biological mechanisms driving these outcomes remain incompletely defined, particularly in the context of intact human skin, where cell diversity and intercellular interactions are preserved. Here, we performed single-cell RNA and ATAC sequencing on paired skin samples from human subjects (n=4), comparing sites treated with clobetasol propionate to vehicle controls. GCs induced distinct, cell-type-specific changes. In immune cells, they suppressed interferon-γ and IL-2/STAT5 signaling, aligning with their established immunosuppressive effects. In fibroblasts, GCs downregulated collagen I and other extracellular matrix components, consistent with their known contribution to dermal atrophy. We observed an unexpected upregulation of NF-κB signaling in both keratinocytes and fibroblasts. This shift may explain why inflammatory skin conditions like rosacea and perioral dermatitis can be exacerbated by topical steroids, as NF-κB activation is known to drive inflammation. We also performed CellChat analysis to examine cell-cell communication. This revealed that GCs induce dynamic changes to intercellular communication, including amplified semaphorin-3a signaling to fibroblasts from melanocytes, adipocytes, and neurons. These intercellular signaling changes highlight the complex cross-talk among resident skin cell types impacted by GCs, shaping their broad biological effects. In summary, our findings define the diverse genetic and intercellular effects of topical GCs in vivo, providing new insights into their mechanisms of action and informing strategies to optimize their use. Joohyun An¹, Elton Tong¹, Bryan Sun¹ 1. Dermatology, University of California Irvine, Irvine, CA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics