Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68+ synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway.

Systemic lupus erythematosus (SLE) is a remarkable heterogeneous autoimmune disease that is sometimes hard to diagnose at the early stage and can lead to premature mortality. Long non‐coding RNAs (lncRNAs) are a class of non‐protein‐coding RNAs greater than 200 nucleotides in length that can regulate gene expression in various human diseases, including SLE. Peripheral blood samples and renal tissue samples from SLE patients were used for study. Abnormally expressed lncRNAs in SLE have been shown to influence several signalling pathways, including the IFN‐I, MAPK and WNT pathways. This can affect cellular phenotypes like cell activation, differentiation skewing, cytokine production and cell apoptosis. Many of the reported lncRNAs may be useful for diagnosing, evaluating progression and predicting potential organ damage in SLE patients. While numerous lncRNAs play important roles in SLE, more basic and clinical studies are warranted to clarify the function of these regulatory molecules and determine their diagnostic value.

The original version of this article contained a mistake in figure 4. There was an error in figure 4H. In these wound healing assays, the figure in group "Pictilisib + Semaphorin 5A" was mistakenly repeated with that in group "MK-2206+Semaphorin 5A" at 24h! The authors apologize for this mistake. There is no impact on the final conclusions. The original article has been corrected.

Background Rheumatoid arthritis (RA) is the most common chronic autoimmune connective tissue disease. However, early RA is difficult to diagnose due to the lack of effective biomarkers. This study aimed to identify new biomarkers and mechanisms for RA disease progression at the transcriptome level through a combination of microarray and bioinformatics analyses.Methods Microarray datasets for synovial tissue in RA or osteoarthritis (OA) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by R software. Tissue/organ-specific genes were recognized by BioGPS. Enrichment analyses were performed and protein-protein interaction (PPI) networks were constructed to understand the functions and enriched pathways of DEGs and to identify hub genes. Cytoscape was used to construct the co-expressed network and competitive endogenous RNA (ceRNA) networks. Biomarkers with high diagnostic value for the early diagnosis of RA were validated by GEO datasets. The ggpubr package was used to perform statistical analyses with Student’s t-test.Results A total of 275 DEGs, including 197 downregulated genes and 78 upregulated genes, were identified between the samples from RA and OA. Among these DEGs, 71 tissue/organ-specific expressed genes were recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that DEGs are mostly enriched in immune response, immune-related biological process, immune system, and cytokine signal pathways. Fifteen hub genes and 4 gene cluster modules were identified by Cytoscape. Eight haematologic/immune system-specific expressed hub genes were verified by GEO datasets, and three genes (granzyme A (GZMA), protein regulator of cytokinesis 1 (PRC1), and threonine/tyrosine kinase protein kinase (TTK)) that have a high diagnostic value for early RA were identified. NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158- miR-212-3p/miR-132-3p/miR-129-5p-TTK might be potential RNA regulatory pathways to regulate the disease progression of early RA.Conclusions This work identified three haematologic/immune system-specific expressed genes, namely, GZMA, PRC1, and TTK, as potential biomarkers for the early diagnosis and treatment of RA and provided insight into the mechanisms of disease development in RA at the transcriptome level. In addition, we proposed that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK, XIST-miR-25-3p/miR-129-5p-GZMA, and TTK_hsa_circ_0077158-miR-212-3p/miR-132-3p/miR-129-5p-TTK are potential RNA regulatory pathways that control disease progression in early RA.