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.<h4>Conclusions</h4>Our findings suggest a potential pathogenic role for S100A4 in psoriasis and highlight previously uncharacterized cell-specific transcriptional landscapes and regulatory mechanisms. Here, S100A4 is linked to Hyperkeratosis.