Transcriptomic characterization of key psoriasis-associated genes based on single-cell RNA-seq and machine learning

Background Psoriasis is a multifaceted skin and systemic disorder driven by a complex interplay of genetic, immunological, and environmental factors. Genetic predisposition plays a pivotal role, with the IL-17/IL-23 immune axis recognized as a central pathogenic pathway. Ongoing research, however, continues to uncover additional critical drivers, cytokines, intracellular signaling networks, and potential therapeutic targets. Methods Single-cell RNA sequencing (scRNA-seq) datasets comprising both psoriatic and healthy samples were obtained from the Gene Expression Omnibus (GEO). Cell-type proportions were estimated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), and weighted gene co-expression network analysis (WGCNA) was applied to explore correlations between cell types and gene signatures. Machine learning algorithms were subsequently employed to identify four psoriasis-associated key genes: DEFB4A , GJB2 , SERPINB3 , and SERPINB13 . Their expression was validated in bulk RNA-seq datasets. Using scRNA-seq data, we further investigated the lesional regulatory roles of these genes and their associated pathway alterations, and we proposed targeted therapeutic strategies. Results A series of algorithms identified 271 hub genes significantly associated with psoriasis lesions and basal cells. Machine learning analysis refined this set to four key genes in psoriasis: DEFB4A , GJB2 , SERPINB3, and SERPINB13 . Conclusions These four psoriasis-associated driver genes were upregulated in lesional skin. We also screened small-molecule compounds targeting these genes, offering potential therapeutic strategies.