Explicating miRNA-mediated regulation of inflammatory pathways in COPD, MS, and lung cancer using explainable artificial intelligence: insights from peripheral blood profiles.

Abstract

Background: Chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), and lung cancer are linked by shared inflammatory pathways and immune dysregulation. miRNAs regulate these processes by influencing gene expression, yet their roles in the molecular mechanisms across neurological and respiratory systems are not fully understood.

Objective: This study aims to identify miRNAs and their target genes regulating inflammatory pathways, advancing the understanding of molecular genetics underlying COPD, MS, and lung cancer.

Methods: miRNA expression data (GSE61741) were analyzed using a Random Forest (RF) model optimized via Grid Search and validated with Stratified K-Fold cross-validation. Synthetic Minority Oversampling (SMOTE) addressed data imbalance, while SHapley Additive exPlanations (SHAP) identified key miRNAs. Functional enrichment and pathway analyses explored miRNA-gene interactions. Single-cell level analysis further validated the cell-specific roles of these genes. An independent dataset (GSE31568) was used for validation.

Results: Key miRNAs, including hsa-let-7c, hsa-miR-454, hsa-miR-92a, and hsa-miR-223, were identified as regulators of hallmark inflammatory genes such as CCL2, IL6, ITGB3, and MYC. These genes are critical for cytokine signaling, epithelial repair, and immune modulation. Single-cell analysis highlighted the role of inflammatory fibroblasts in localized inflammation and tissue remodeling. The RF model achieved an accuracy of 81.58%, validated at 82.55%. Pathway analysis emphasized cytokine-cytokine receptor interactions and shared pathways between neurological and respiratory diseases.

Conclusions: This study identifies miRNAs and their target genes as critical regulators of inflammation in COPD, MS, and lung cancer. Single-cell insights and pathway enrichment provide a comprehensive view of shared molecular mechanisms, contributing to biomarker discovery and therapeutic strategies for precision medicine in inflammatory diseases.