MicroRNA Networks in Systemic Lupus Erythematosus: From Compartment-Specific Biomarkers to Precision Immune Endotypes

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease in which defective immune tolerance, nucleic-acid sensing, type I interferon activation, T- and B-cell dysregulation, immune-complex formation and tissue injury interact as a self-reinforcing network. MicroRNAs (miRNAs) are short non-coding RNAs that fine-tune post-transcriptional gene expression and can simultaneously regulate multiple nodes of this network; their relevance to SLE therefore extends beyond simple differential expression to encompass epigenetic remodeling, extracellular-vesicle (EV) communication, inflammatory signaling and organ-specific injury. This critical narrative review synthesizes evidence published between 2020 and 2026 concerning miR-146a, miR-21, miR-155, miR-126, miR-150, miR-181a, miR-223, miR-125-family members, the miR-17~92 cluster and emerging EV-associated candidates, with particular emphasis on the compartment-dependence of miR-146a and on urinary/plasma EV biomarkers in lupus nephritis (LN). A regionally important Middle Euphrates cohort (Shlash et al.) is incorporated alongside international evidence to illustrate both the value and the limits of single-cohort biomarker studies. Across compartments, the literature supports miRNAs as important network regulators but does not support any single miRNA as a universal SLE biomarker: the direction and magnitude of change vary with cell type, biofluid, disease activity, treatment exposure and analytical workflow. We argue that clinical translation should move from single-miRNA discovery toward standardized, compartment-specific, multi-miRNA signatures that are analytically validated per the Minimum Information for Publication of Quantitative Real-Time PCR Experiments guidelines (MIQE 2.0), EV-characterized where relevant per the Minimal Information for Studies of Extracellular Vesicles guidelines (MISEV2023), and integrated with interferon activity, immune-cell endotype, renal biomarkers and longitudinal outcomes in prospective multicenter cohorts.