Rheumatoid arthritis (RA) is a systemic disease dominated by inflammatory synovitis. RA synovial macrophages tend undergo M1-type macrophage polarization. Then, polarized M1-type macrophages secrete abundant pro-inflammatory cytokines, causing joint and cartilage destruction. N6-methyladenosine (m6A) methylation modification, circular RNA (circRNA), microRNA (miRNA), messenger RNA (mRNA), etc. are involved in the inflammatory response of RA. We found that there is an imbalance of inflammatory polarization in RA, which is manifested by a sharp increase in inflammatory markers and a high inflammatory response. Here, we show that RA was closely associated with low expression of circ_0066715. The overexpression of circ_0066715 significantly increased the ETS1 levels in RA-FLS cells, decreased cytokine secretion by M1-type macrophages, elevated M2-type cytokines, and inhibited FLS proliferation. Interestingly, the overexpression of miR-486-5p significantly suppressed the attenuation of the cell function and the effect on M1 macrophage polarization caused by circ_0066715 positive expression. WTAP may be involved in the methylation process of ETS1 in RA. ETS1 m6A methylation levels were altered upon WTAP intervention. The overexpression or interference of circ_0066715 decreased or increased WTAP expression. Our findings provide a novel circRNA/miRNA/mRNA regulatory axis and m6A regulatory mechanism involved in the process of RA macrophage polarization, thereby providing a powerful diagnostic and therapeutic strategy for RA treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that is diagnosed mainly on the basis of patient signs, symptoms, and laboratory indices. However, the exact causes of RA are unclear. Moreover, there is a lack of any method of dynamically evaluating the efficacy of the medication administered to treat RA. Here, we applied a random walk model to reveal the compatibility among the various constituents of traditional Chinese medicine and evaluate their therapeutic efficacy against RA. Drugs commonly used to treat RA were investigated using cluster analysis. The association rule analysis was applied to identify compatibilities among the constituents. A random walk model was developed to evaluate drug efficacy based on an in‐house database comprising the clinical records of 9,408 RA patients. Frequently administered medicines were combined into three correlated sets. The evaluation based on the random walk method showed that the drug combination improved ESR, CRP, C3, C4, and IgA more effectively than any single drug. The present study demonstrated that the TCM constituents complement each other and various combinations of them produce different therapeutic effects on RA treatment.

N6-methyladenosine (m6A) modification is the most prevalent chemical modification in eukaryotic mRNA and is associated with the development of various immune diseases. However, the role of m6A methylation in rheumatoid arthritis (RA) development is unclear. We preliminarily explored the role of m6A methylation-related mRNAs in RA for its clinical application. The discovery of m6A methylation-modifying genes in this study may provide a fresh perspective on the development of drugs for RA treatment. High-throughput sequencing combined with methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing were used to assess whole-transcriptome m6A modifications in the synovium of patients with RA. The relationship between m6A-modified target genes and RA inflammation and macrophages was determined. The expression of the m6A-modified significant transcript-enriched inflammatory signaling pathway was assessed through animal experiments. Differentially expressed m6A genes were correlated with macrophage activation involved in immune response, vascular endothelium, MAPK signaling pathway, PI3KAkt signaling pathway, and other inflammatory processes. Furthermore, combined analysis with m6A-seq and RNA-seq revealed 120 genes with significant changes in both m6A modification and mRNA expression. We selected the top 3 candidate mRNAs that were upregulated and downregulated simultaneously. The expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) mRNA and protein in RA patients was lower than that in healthy control (HC). SHC-binding protein 1 (SHCBP1) and neurexophilin-3 (NXPH3) mRNA expressions were increased in RA patients. The expression of M1 macrophages was increased in RA patients. RA markers are such as rheumatoid factor (RF) and peptide containing citrulline (CCP). Further animal experiments showed that the expression of synovial MAPK, PI3K, and Akt1 proteins in the RA model was increased, and the PTEN, p-PTEN protein expression was decreased. PI3K, Akt1, PTEN, and p-PTEN were correlated to RA joint inflammation. This study revealed a unique pattern of differential m6A methylation modifications in RA and concluded that m6A modification is related to the occurrence of RA synovial inflammation.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. It has a high prevalence worldwide, significantly impacting patients ‘ quality of life. There are still numerous obstacles and problems in the treatment of this disease. In the RA patients and RA animal models, the inflammatory response mainly involves abnormal activation of immune cells, such as T cells and macrophages. These cells release pro-inflammatory cytokines and trigger autoimmune reactions, ultimately causing irreversible joint tissue damage. The pathogenesis of RA is complex, involving genetic and environmental factors. Genetic factors increase the risk of disease, while environmental factors, such as infection and smoking, can trigger the onset of disease. An in-depth study of its pathogenesis and new therapeutic targets is of great significance in improving the therapeutic effect of RA. Recently, m6A methylation, an RNA modification method, has played an important role in regulating gene expression and disease progression. This modification significantly regulates immune inflammatory responses in RA, providing new insights for potential therapeutic approaches. Moreover, ferroptosis and cuproptosis, two new forms of cell death, have gradually been recognized to play an important role in the pathogenesis of RA. Ferroptosis is characterized by an imbalance in intracellular iron homeostasis and the production of reactive oxygen species, while cuproptosis involves the accumulation and metabolic abnormalities of intracellular copper. These processes play a key role in the immune inflammatory response of RA and have become potential therapeutic targets. The current review discusses the research progress of m6A methylation, ferroptosis, and cuproptosis in the pathogenesis of RA and elucidates their interactions. An in-depth understanding of these new targets might provide new strategies and drug design ideas for the treatment of RA, thereby improving the prognosis and quality of life of RA patients.

ETS-1, a key member of the Erythroblast Transformation-Specific (ETS) transcription factor family, plays an important role in cell biology and medical research due to its wide expression profile and strong transcriptional regulation ability. It regulates fundamental biological processes, including cell proliferation, differentiation, and apoptosis, and is involved in tumorigenesis and metastasis, promoting malignant behaviors such as angiogenesis, matrix degradation, and cell migration. Given the association between ETS-1 overexpression and the aggressive characteristics of multiple malignancies, it represents a promising therapeutic target in cancer treatment. This study aims to systematically analyze the role of ETS-1 within the tumor immune microenvironment, elucidating its mechanisms in cancer initiation, progression, and metastasis. It also investigates the differential expression of ETS-1 across tumor tissues and adjacent normal tissues, exploring its potential as a molecular marker for tumor diagnosis and prognosis.