LncRNA-MEG3/miR-93-5p/SMAD7 axis mediates proliferative and inflammatory phenotypes of fibroblast-like synoviocytes in rheumatoid arthritis.

Synovial hyperplasia, inflammation and immune cell infiltration are the central pathological basis of rheumatoid arthritis (RA). Nonetheless, the cellular, molecular and immunological mechanisms of RA remain poorly understood. An integrated analysis of single-cell RNA (scRNA) and bulk RNA sequencing datasets‌ aimed to unravel the cellular landscape, differentiation trajectory, transcriptome signature, and immunoinfiltration feature of RA synovium. Multilevel experiments were conducted to investigate the role and mechanism of MEG3 in the aggravation and reversal of RA. We screened 97 intergroup differential genes of single-cell transcriptome profiles in the RA versus PsA comparison, which were principally associated with metabolism, inflammation, and proliferation. Clustering and annotation analysis defined 7 key cell subpopulations (monocytes, epithelial cells, CD8T cells, granulocytes, fibroblasts, HSC_CD34, and B cells) and their marker genes. Pseudotime analysis demonstrated that fibroblasts could be the end-effector cells, and that downregulation of MEG3 may be responsible for cell differentiation and state transition, followed by the malignant manifestations in the RA synovium. Mechanistically, overexpression of MEG3 could alleviate the proliferative and inflammatory phenotypes of RA synovial fibroblasts by competitively sponging miR-93-5p to promote SMAD7 expression. Taken together, our findings underscore the biological significance of MEG3/miR-93-5p/SMAD7 axis, providing valuable insights into the pathogenesis of RA.