Integrative Transcriptomic and Machine-Learning Analysis Reveals Immune-Inflammatory and Stress-Response Alterations in MRONJ

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies, yet its molecular mechanisms remain poorly defined. The present study employed an analysis of microarray data (GSE7116) from peripheral blood mononuclear cells of patients with multiple myeloma, myeloma patients with MRONJ, and healthy controls. Differentially expressed genes were identified using the limma package, followed by functional enrichment analysis, weighted gene co-expression network analysis, and LASSO regression and CytoHubba network ranking. The predictive performance was validated by means of nested cross-validation, Firth logistic regression, and safe stratified 0.632+ bootstrap ridge regression. The profiling revealed distinct gene expression patterns between the groups: the upregulation of ribosomal and translational pathways, as well as the suppression of neutrophil degranulation and antimicrobial defense mechanisms, and identified key candidate genes, including <i>PDE4B</i>, <i>JAK1</i>, <i>ETS1</i>, <i>EIF4A2</i>, <i>FCMR</i>, <i>IGKV4-1</i>, and <i>XPO7</i>. These genes demonstrated substantial discriminatory capability, with an area under the curve ranging from 0.95 to 0.99, and were found to be functionally linked to immune system dysfunction, cytokine signaling, NF-κB activation, and a maladaptive stress response. These findings link MRONJ to systemic immune-inflammatory imbalance and translational stress disruption, offering novel insights and potential biomarkers for diagnosis and risk evaluation.