Abstract
BACKGROUND: Psoriasis is a common autoimmune skin disease with high morbidity and associated complications, characterized by epidermal hyperplasia and cutaneous infiltration of immune cells. The role of S100A4, a key antimicrobial peptide, is highly expressed in psoriatic skin and has aroused considerable interest in recent years, yet its specific function and associated molecular mechanisms remain elusive. METHODS: Using CRISPR/Cas9 to generate S100a4 gene knockout mice, imiquimod was continuously applied to the back skin to induce the psoriasis disease model. Single-cell RNA sequencing (scRNA-seq) was employed to investigate changes in epidermal cell composition and gene expression profiles in mice subjected to different treatments. Multiple bioinformatics analyses were conducted to elucidate the biological role of S100A4 in psoriasis pathogenesis. RESULTS: We observed that S100a4 knockout mice exhibited significant pathological improvement in psoriasis-like lesions, including reduced inflammatory cell infiltration and decreased epidermal hyperplasia. The results of scRNA-seq revealed that after S100a4 knockout, the pathologically relevant keratinocyte subpopulation was significantly reduced, and the related tumor necrosis factor (TNF) and interleukin-17 (IL-17) signal transducers and activator of keratinization were downregulated. Moreover, S100a4 depletion moderated the abnormal proliferation and differentiation dynamics of keratinocytes. Additionally, Klf9-mediated transcriptional dysregulation of Krt15 in keratinocytes was identified as a key driver of hyperkeratosis, while S100a4 deficiency contributed to restoring cellular homeostasis in this process. CONCLUSIONS: Our findings suggest a potential pathogenic role for S100A4 in psoriasis and highlight previously uncharacterized cell-specific transcriptional landscapes and regulatory mechanisms. Our results provide novel insights into the complex pathology of psoriasis and could offer important clues for the development of new targeted therapeutic strategies.