Shared Immunoregulatory Gene Module Across Psoriatic Skin and Non-Receptive Endometrium

Abstract Epidemiologic studies suggest an association between psoriasis and adverse reproductive outcomes. Psoriasis is a chronic inflammatory disorder, and recurrent implantation failure (RIF) is increasingly linked to dysregulated immune states in the endometrium during the implantation window. To determine whether these conditions share a conserved immunoregulatory program, RNA sequencing datasets were integrated from psoriatic lesional and non-lesional skin and from mid-secretory endometrium of fertile women and women with RIF. Differential expression analysis identified 497 genes dysregulated across tissues, including 421 coding genes. Shared genes were mapped to a protein interaction network to detect densely connected modules, followed by functional and transcription factor motif enrichment. Supervised classification models were trained using module genes and evaluated across validation schemes. Immune cell enrichment inferred from bulk profiles supported tissue-specific remodeling, with broad immune infiltration in psoriatic lesions and selective lineage shifts in RIF endometrium. Network analysis revealed a dominant 29 gene module enriched for chemokine and cytokine signaling, extracellular matrix remodeling, and immunoregulatory signaling. Increased module activity was observed in psoriatic lesions, whereas attenuated activity was detected in endometrial samples, consistent with a dysregulated immune state in RIF. Motif enrichment highlighted 13 immune-related transcriptional regulators. Module-based models supported biologically meaningful separation in both comparisons, with area under the receiver operating characteristic curve up to 0.96 in endometrium and 0.97 in skin. Together, a shared immunoregulatory network module associated with chronic cutaneous inflammation and altered endometrial receptivity was identified, providing a foundation for network-based biomarker development in RIF.