Explainable machine learning-based identification of transcriptomic biomarkers in CD1c+ dendritic cells for non-infectious uveitis: an integrative analysis of bulk RNA-seq data

Introduction Non-infectious uveitis (NIU) is a leading cause of intraocular inflammation, and the underlying immunological mechanisms remain incompletely understood. This study aims to classify NIU at the molecular level and interpret its biological mechanisms by applying machine learning and explainable artificial intelligence (XAI) methods to transcriptomic data from CD1c+ conventional dendritic cells type 2 (cDC2) isolated from the peripheral blood of NIU patients. Methods Two independent cohorts (GSE194060 and GSE195501; n = 78) from the Gene Expression Omnibus (GEO) database were integrated using a strict, leakage-free pipeline. Batch correction and analysis of variance (ANOVA)-based feature selection, applied exclusively on the training set, identified the 20 most informative genes from 8,815 candidates. L2-regularized logistic regression, support vector machines, and random forest models were compared. The model’s biological basis was elucidated using Shapley Additive Explanations (SHAP) analysis and comprehensive pathway enrichment analyses. Results The L2-regularized logistic regression model achieved the best performance with a nested cross-validation area under the curve (AUC) of 0.863, test AUC of 0.855, accuracy of 81.2%, recall of 90.9%, and F1-score of 0.870. Leave-One-Dataset-Out (LODO) validation supported cross-platform generalizability (mean AUC: 0.82). Permutation testing confirmed the model’s statistical significance (p = 0.005). SHAP analysis identified CD180 and TLR7 as the most important biomarkers. Pathway enrichment analysis revealed significant enrichment in chemokine receptor activity, MYD88-mediated signaling, Toll-like receptor cascades, and G protein-coupled receptor (GPCR) signaling pathways. Conclusion These findings demonstrate the potential of XAI to elucidate disease mechanisms from transcriptomic data and present an interpretable 20-gene signature as a candidate diagnostic biomarker panel for non-infectious uveitis that warrants further clinical validation.