A mitoxyperiosis-associated gene signature correlates with immune disturbance and provides a potential diagnostic biomarker for systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with complex pathogenesis. Mitochondrial dysfunction and aberrant cell death are key drivers, but the mitoxyperiosis pathway has not been explored in SLE. This study aimed to evaluate mitoxyperiosis-associated gene expression in SLE, construct a diagnostic model, identify molecular subtypes, and characterize immune-inflammatory correlations. METHOD: Differentially expressed mitoxyperiosis-related genes were identified in the discovery cohort (GSE318067) and validated in an independent cohort (GSE61635). A logistic regression model was built using the intersecting genes and evaluated by receiver operating characteristic (ROC), calibration, and decision curve analyses in the merged dataset, followed by external validation in GSE112943. Consensus clustering, immune infiltration, cytokine correlations, Weighted Gene Co-expression Network Analysis (WGCNA), and enrichment analyses were performed. Single-cell RNA-sequencing data (GSE224198) were utilized to validate cell-type-specific expression and predict transcriptional consequences via virtual perturbation. RESULTS: The mitoxyperiosis gene set score was significantly elevated in SLE. Four genes (BAK1, MYD88, RICTOR, and TLR4) were consistently upregulated across cohorts and retained as the diagnostic signature. The composite model showed excellent discrimination (area under the ROC curve (AUC) = 0.897 in training, 0.955 in validation). Two subtypes were identified: SC1 (adaptive-dominant) and SC2 (innate-dominant), the latter with a more pro-inflammatory profile. Single-cell analysis revealed distinct cell type specific expression patterns, and virtual perturbation identified altered regulon activities. CONCLUSIONS: This first comprehensive evaluation identifies a four-gene mitoxyperiosis-associated signature with potential diagnostic utility in SLE and reveals two immune-inflammatory subtypes that may inform patient stratification and guide future studies. Key Points • This is the first comprehensive evaluation identifying a mitoxyperiosis-associated gene expression signature in SLE. • A four-gene signature (BAK1, MYD88, RICTOR, and TLR4) associated with the mitoxyperiosis pathway may serve as a potential diagnostic and risk-prediction tool for SLE. • Consensus clustering reveals two immune-inflammatory subtypes: SC1 and SC2, with the SC2 subtype characterized by broader immune activation and a more pro-inflammatory microenvironment.