Revealing the regulation of allergic asthma airway epithelial cell inflammation by STEAP4 targeting MIF through machine learning algorithms and single-cell sequencing analysis

Abstract

Asthma comprises one of the most common chronic inflammatory conditions, yet still lacks effective diagnostic markers and treatment targets. To gain deeper insights, we comprehensively analyzed microarray datasets of airway epithelial samples from asthmatic patients and healthy subjects in the Gene Expression Omnibus database using three machine learning algorithms. Our investigation identified a pivotal gene, STEAP4. The expression of STEAP4 in patients with allergic asthma was found to be reduced. Furthermore, it was found to negatively correlate with the severity of the disease and was subsequently validated in asthmatic mice in this study. A ROC analysis of STEAP4 showed the AUC value was greater than 0.75. Functional enrichment analysis of STEAP4 indicated a strong correlation with IL-17, steroid hormone biosynthesis, and ferroptosis signaling pathways. Subsequently, intercellular communication analysis was performed using single-cell RNA sequencing data obtained from airway epithelial cells. The results revealed that samples exhibiting low levels of STEAP4 expression had a richer MIF signaling pathway in comparison to samples with high STEAP4 expression. Through both in vitro and in vivo experiments, we further confirmed the overexpression of STEAP4 in airway epithelial cells resulted in decreased expression of MIF, which in turn caused a decrease in the levels of the cytokines IL-33, IL-25, and IL-4; In contrast, when the STEAP4 was suppressed in airway epithelial cells, there was an upregulation of MIF expression, resulting in elevated levels of the cytokines IL-33, IL-25, and IL-4. These findings suggest that STEAP4 in the airway epithelium reduces allergic asthma Th2-type inflammatory reactions by inhibiting the MIF signaling pathway.