Machine learning and in vivo experimentation have identified three genes strongly linked to IL-17A-mediated inflammation in psoriasis, according to new research published in Scientific Reports.
"It is widely acknowledged that Th17/IL-17A axis plays a key role in the pathogenesis of psoriasis," the authors wrote in Nature Scientific Reports. "However, numerous regulatory genes upstream of the pathway remain undiscovered, creating a knowledge gap in our understanding of the genetic aspects of the Th17/IL-17A axis."
Researchers drew upon data from four gene expression datasets (GSE14905, GSE13355, GSE121212, and GSE151177) and used weighted gene co-expression network analysis, gene set enrichment analysis, and three machine learning models (LASSO regression, support vector machine, and random forest) to isolate differentially expressed genes that correlated with IL-17A pathway activity.
According to the data, CCR7, IL2RG, and PLEK emerged as the strongest candidates, with all three showing increased expression in lesional psoriatic tissue vs. to healthy controls. The findings were confirmed across multiple datasets. All three genes were showed elevated expression levels in the diseased tissue. Selectively silencing PLEK expression using siRNA in the mouse model reduced both inflammatory markers and clinical skin symptoms. Additional single-cell RNA sequencing showed PLEK was expressed primariliy in CD4-positive T cells, dendritic cells, and natural killer cells.
"Our study identified three novel genes in the context of psoriasis and validated their close relationship with the Th17/IL-17A signaling pathway," concluded the research team. "Notably, our report marks the first mention of PLEK as a disease-causing gene in psoriasis, opening new avenues for further exploration and potential treatment strategies for this condition."
Source: Zhang Y, et al. Scientific Reports. 2025. Doi:10.1038/s41598-025-87556-w