Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with incompletely understood pathogenesis, characterized by immune dysregulation and multi-organ involvement. Long non-coding RNAs (lncRNAs) modulate immune activation and cytokine release in autoimmunity. Dendritic cells (DCs), as antigen-presenting cells, regulate T/B cell function and immune homeostasis. Our prior high‑throughput sequencing showed reduced lncRNA NONHSAT173448.1 expression in SLE patients. This study aimed to explore its regulatory role in DC phenotype/function and its potential as a biomarker and therapeutic target in SLE.

SLE patients meeting the ACR/EULAR classification criteria and healthy controls were enrolled. Peripheral venous blood was collected to isolate peripheral blood mononuclear cells (PBMCs). Different immune cell subsets were sorted from PBMCs using immunomagnetic beads. In this study, DCs were mainly induced in vitro from monocytes derived from PBMCs. Different immune cell subsets were sorted from PBMCs using immunomagnetic beads. In this study, DCs were mainly induced in vitro from monocytes derived from PBMCs.Different immune cell subsets were sorted from PBMCs using immunomagnetic beads. In this study, DCs were mainly induced in vitro from monocytes derived from PBMCs. Different immune cell subsets were sorted from PBMCs using immunomagnetic beads. In this study, DCs were mainly induced in vitro from monocytes derived from PBMCs. The expression level of lncRNA NONHSAT173448.1 was verified by qRT‑PCR, and its correlation with SLEDAI‑2K scores and immune‑related factors was analyzed. The effect of NONHSAT173448.1 on dendritic cell differentiation was explored via transfection assays and flow cytometry, and functional changes in DC subsets were evaluated by measuring the proportions of plasmacytoid dendritic cells (pDCs), inflammatory dendritic cells (DC3s), and conventional dendritic cells 2 (cDC2s). The role of NONHSAT173448.1 in T cell differentiation was assessed by co‑culturing NONHSATAT173448.1‑overexpressing DCs with naive CD4+ T cells. In addition, bioinformatic analyses including proteomic analysis and GO analysis were performed to predict the target genes and regulatory networks of lncRNA NONHSAT173448.1, and the ribosomal protein L5 (RPL5) gene was identified. Cell models with RPL5 overexpression and silencing were constructed, and qRT‑PCR was used to detect the relationship between RPL5 expression and the level of lncRNA NONHSAT173448.1 in SLE patients and healthy controls. We also explored the effect of interleukin‑6 (IL‑6) on the expression of lncRNA NONHSAT173448.1 in DCs from SLE patients.

QRT-PCR confirmed that lncRNA NONHSAT173448.1 expression was significantly reduced in PBMCs from SLE patients, and negatively correlated with disease progression. Among the immune cell subsets sorted from PBMCs by magnetic beads, the expression of this gene was particularly significantly decreased in DCs of patients. DCs were first induced in vitro from monocytes that had been sorted out from the PBMCs of SLE patients using immunomagnetic bead separation technology. These in vitro-induced DCs were randomly divided into three groups: the group transfected with a vector overexpressing lncRNA NONHSAT173448.1 was named Group M, the group transfected with empty plasmid was named Group C, and the group without transfection treatment was named Group N. Through flow cytometry, we can observe a marked reduction in pDCs and DC3s, accompanied by an increase in cDC2s. Subsequent co‑culture with naive T cells showed that overexpression of NONHSAT173448.1 in DCs led to increased regulatory T (Treg) cells and decreased activated T cells. Through the construction of gene knockout and overexpression vectors, it was confirmed that RPL5 is a downstream target of NONHSAT173448.1, and that NONHSAT173448.1 can stabilize the expression of RPL5. Furthermore, IL‑6 was identified as an inhibitor of lncRNA NONHSAT173448.1 expression in DCs from SLE patients, with higher serum IL‑6 levels correlating strongly with disease activity

Our study demonstrates that lncRNA NONHSAT173448.1 plays a key role in regulating the phenotype and function of DCs in SLE, affects T cell differentiation, and may serve as a biomarker for disease activity. The regulation of ribosomal protein L5 (RPL5) by NONHSAT173448.1, together with the inhibitory effect of IL‑6 on the expression of this lncRNA, provides novel insights into the pathogenesis of SLE and may pave the way for targeted therapeutic interventions. However, this study has several limitations, including a small sample size, a single‑center design, and lack of validation in animal models. Further studies with expanded multi‑center cohorts are warranted to explore its detailed regulatory mechanisms and provide more reliable experimental support for the precision management of SLE.