Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovitis and progressive joint destruction. While accumulating evidence highlights the critical roles of long non-coding RNAs (lncRNAs) in RA pathogenesis, the functional contributions of many lncRNAs remain poorly understood.

 Whole-transcriptome sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 5 RA patients and 5 healthy controls to identify differentially expressed lncRNAs. Candidate lncRNAs were selected based on fold-change and expression levels, then validated via quantitative real-time PCR (qRT-PCR) in an expanded cohort comprising 56 RA patients, 18 systemic lupus erythematosus (SLE) patients, 20 primary Sjögren's syndrome (pSS) patients, and 39 healthy controls. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Bioinformatic predictions were employed to explore potential miRNA–mRNA–protein interaction networks and functional mechanisms.

RNA sequencing identified 2,162 differentially expressed lncRNAs in RA PBMCs compared to healthy controls, with 1,212 upregulated and 950 downregulated. Among six lncRNAs selected for validation, NR_125715.1 and ENST00000413791 showed significant expression alterations in RA patients. Notably, NR_125715.1 demonstrated high diagnostic accuracy (AUC = 0.8610) and exhibited RA-specific expression patterns when compared to SLE and pSS disease controls. Furthermore, NR_125715.1 expression correlated positively with rheumatoid factor (r = 0.297, p = 0.036) and anti-cyclic citrullinated peptide antibodies (r = 0.3809, p = 0.0041). Bioinformatic analysis suggested that NR_125715.1 may function as a competing endogenous RNA (ceRNA) by sponging miR-6756-3p to regulate E2F2 expression, and may also interact with the FUS protein, potentially influencing RNA metabolism and inflammatory signaling pathways. No m6A methylation sites or CpG islands were identified in this lncRNA.

 Our findings indicate that NR_125715.1 contributes to RA pathogenesis by acting as a ceRNA for miR-6756-3p (which targets E2F2) and by binding to the FUS protein. These results provide new insights into the epigenetic mechanisms underlying RA and highlight NR_125715.1 as a promising diagnostic biomarker and potential therapeutic target.