Integrative MultiOmics and Machine Learning Reveal Peroxiredoxin 4 as a Critical Hub Governing Mitochondrial...

Periodontitis, a highly prevalent chronic inflammatory disease, progressively destroys tooth-supporting tissues, ultimately leading to tooth loss, and significantly increases systemic risks such as cardiovascular disease and diabetic complications. Current mechanical therapies effectively control clinical symptoms but fail to eradicate pathogenic microenvironments or restore periodontal homeostasis. Mitochondrial dysfunction is a critical driver of periodontitis progression; however, the regulatory mechanisms of mitochondria-related genes remain poorly defined.

This study integrated bulk transcriptome sequencing (bulk RNA-seq) and single-cell RNA-seq (scRNA-seq) analyses to identify mitochondrial dysfunction-associated immune cell alterations in periodontitis. Key mitochondria-related genes inducing disease progression were pinpointed through non-negative matrix factorization (NMF) and weighted gene coexpression network analysis (WGCNA). By integrating ten machine learning algorithms with experimental validation using real-time quantitative polymerase chain reaction (qPCR) and immunofluorescence, peroxiredoxin 4 (PRDX4) was identified as the most crucial hub gene governing mitochondrial homeostasis in periodontitis.

Patient stratification based on PRDX4 expression revealed upregulated B cell-related pathways. Pseudotime analysis demonstrated a synchronized upregulation of PRDX4 and B cell signature genes during late-stage disease progression. scRNA-seq and immunofluorescence confirmed PRDX4 upregulation in B cells, particularly in plasma cells and memory B cells, and indicated its involvement in B cell differentiation. Experiments in a mouse model further validated the conserved functional role of PRDX4 in regulating B cells during periodontitis. Finally, we screened traditional Chinese medicinal compounds and identified aloe as a potential PRDX4 inhibitor.

These findings establish PRDX4 as a key regulatory node linking mitochondrial dysfunction to periodontitis pathogenesis, providing insights into mitochondria-related genes and potential therapeutic strategies.