The emerging role of noncoding RNAs in systemic lupus erythematosus: new insights into the master regulators of disease pathogenesis

**Background:** Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by loss of immune tolerance, autoantibody production, and multi-organ inflammation. Its etiology involves genetic, environmental, hormonal, and epigenetic factors. Noncoding RNAs (ncRNAs)—including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs)—have emerged as critical epigenetic regulators that influence gene expression and immune signaling pathways. This narrative review aims to summarize the roles of ncRNAs in SLE pathogenesis and their potential as biomarkers and therapeutic targets.

**Methods:** The authors conducted a narrative review of the literature, synthesizing findings from clinical studies, animal models, and in vitro experiments that investigated the expression and function of ncRNAs in SLE. The review covers miRNAs (e.g., miR-181, miR-21, miR-155, miR-146a, miR-210, miR-29a, miR-125b, miR-199-3p, miR-153-3p), lncRNAs (e.g., NEAT1, TUG1, GAS5, Lnc-DC, MIAT, MALAT-1), and circRNAs. It also discusses relevant signaling pathways (NF-κB, IFN-I, TGF-β, STAT, PI3K/Akt/mTOR, MAPK) and clinical correlations.

**Key Results:** The review reports that multiple miRNAs are dysregulated in SLE patients compared with healthy controls. For example, miR-181a levels were significantly higher in plasma of SLE patients (100 patients vs. 40 controls) and associated with disease severity. miR-21 expression was increased in CD4+ T cells from SLE patients, especially those with low complement C3. miR-155 showed variable results: some studies found upregulation in peripheral blood (40 SLE vs. 32 controls) while others reported downregulation in serum/urine (40 SLE vs. 30 controls). miR-146a was consistently downregulated in SLE patients (e.g., 88 SLE vs. 30 controls) and linked to renal injury and MSC senescence. miR-210 and HIF1α were upregulated in CD4+ T cells of lupus-prone mice. Among lncRNAs, NEAT1 was upregulated in PBMCs of SLE patients (97 SLE vs. 50 controls) and correlated with Th1/Th2 imbalance and monocyte activation. GAS5 expression was decreased in PBMCs and T cells of SLE patients (302 SLE vs. 396 controls) and associated with disease activity; however, one study reported increased GAS5 in CD4+ T cells (45 SLE patients). TUG1 was downregulated in SLE PBMCs (85 SLE vs. 95 controls) and negatively associated with NF-κB p65. MALAT-1 was upregulated in PBMCs and monocytes (36 SLE vs. 45 controls) and increased IL-21 secretion. CircRNAs such as hsa-circ-0082688 and hsa-circ-0008675 were elevated in SLE patients with renal involvement. The review also notes that ncRNAs influence key pathways: miR-181b targets IFNA1; miR-155 regulates TLR and IFN signaling; miR-146a inhibits NF-κB; GAS5 sponges miR-92a-3p to regulate E4BP4; and NEAT1 activates IFN-I signaling via BAFF.

**Clinical Implications:** The dysregulation of ncRNAs in SLE offers potential for novel diagnostic biomarkers and therapeutic targets. For instance, miR-21, miR-155, and miR-146a may serve as biomarkers for disease activity and organ involvement. Targeting ncRNAs—e.g., restoring miR-146a or inhibiting miR-21—could modulate immune responses and reduce inflammation. LncRNAs like GAS5 and NEAT1 may also be exploited for therapy. However, the review emphasizes that most findings are correlative and require validation in larger cohorts. The complexity of ncRNA networks and their context-dependent roles necessitate further mechanistic studies and clinical trials to translate these insights into clinical practice.