Gout is a metabolic disease, the main pathological mechanism of gout is uric acid metabolism disorders, resulting in excessive production or insufficient excretion of uric acid in the body, and then the deposition of uric acid in the body to form urate crystals [12], in addition, the occurrence of gout is closely related to the inflammatory response, urate crystals deposited in joints and soft tissues and other parts, will cause inflammatory reactions, so that the tissues in the lesion area are damaged and destroyed, while releasing a series of inflammatory factors and cytokines, such as IL-1β, TNF-α, IL-6, etc. Further promotes the persistence of the inflammatory response [13]. In recent years, lncRNA-related research has attracted more and more attention, and studies have confirmed that lncRNA plays an important role in gene regulation, cell proliferation, metastasis and apoptosis [14], in the study of gout, some non-coding RNAs may be involved in the regulation of pathological processes [15], and interact with other biological processes, so it is necessary to explore the pathogenesis of gout from the perspective of lncRNA.
Through bioinformatics analysis of the dataset, this study screened the differential lncRNAs of gout and control populations, lncRNA and mRNA share the same microRNA binding site in the cytoplasm, and affect the expression of targeted mRNA through competitive binding of miRNA [16], after competitive binding of miRNA, lncRNA can regulate the stability and translation of mRNA, further affecting the gene expression and regulation of cells, for example, in some cases, Upregulation of lncRNA can enhance the expression of target genes by regulating miRNA activity to reduce the binding of miRNAs to target genes. In other cases, down-regulation of lncRNAs can increase the binding of miRNAs to target genes, thereby inhibiting the expression of target genes [17]. These different regulatory modalities make lncRNA play a complex and diverse role in ceRNA networks, and more in-depth research is needed to understand its mechanisms and functions.
After the enrichment analysis of differential lncRNA, according to the results of GO analysis, the mRNA regulated by differential lncRNA has significant functions in protein phosphorylation, DNA transcription activator, SMAD protein binding activity, cysteine peptidase activity, receptor-regulated SMAD protein binding activity and protein phosphatase activity, protein tyrosine/serine/threonine phosphatase is an important class of enzymes, which play a role in regulating protein phosphorylation status in cells. The activity of part of the phosphatase may affect the synthesis, secretion and metabolism of uric acid, thereby affecting the balance of uric acid levels in the body, and eventually leading to the occurrence of gout, Qadri et al. [18] have shown that the activity level of protein phosphatase 2A (PP2A) is related to the occurrence of gout, and the decrease in the activity level of PP2A will lead to an increase in the degree of phosphorylation of related enzymes in the purine nucleotide metabolic pathway, which in turn promotes the synthesis and secretion of uric acid, thereby increasing the level of uric acid in the body, leading to the occurrence of gout; DNA transcriptional activator plays an important role in the transcription and expression regulation of genes, and some transcription factors such as NF-κB and AP-1 can aggravate the inflammatory response of gout by regulating the expression of inflammatory factors, thereby aggravating the condition of gout [19]. In addition, DNA transcription activators can also affect bone destruction and repair in gouty arthritis by regulating the expression of genes related to bone resorption and bone formation [20]. SMAD protein binding activity plays an important role in TGF-β signaling pathway [21, 22], SMAD protein binding activity plays an important role in TGF-β signaling pathway, Liu et al. [23] research shows that Smad 3 is an important member of TGF-β/Smad pathway, closely related to the expression and function of human uric acid transporter 1 (hURAT1), and may regulate uric acid metabolism and the occurrence of gouty arthritis. Cysteinyl cathepsins are a class of proteases that play an important role in inflammatory and immunomodulatory processes [24]. Studies have shown that cysteine peptidases such as Cathepsin S and Cathepsin B are involved in the inflammatory response and bone destruction processes in gouty arthritis and may influence the condition of gout by activating NLRP3 inflammasome and promoting the release of inflammatory factors [25, 26].
In terms of KEGG pathway analysis, the differential lncRNA was significantly enriched in Toll-like receptor (TLR), T cell receptor (TCR), TNF signaling pathway, apoptosis-related pathway and MAPK signaling pathway, which are involved in the occurrence and development of gout, among which TLR can activate IL-1β pathway and inflammatory response [27], and TCR plays an important role in T cell-mediated inflammatory response [28]. The MAPK signaling pathway can induce inflammatory response and immune regulation by activating the NF-κB pathway and other factors [29], and the upregulated lncRNA-regulated mRNA is enriched in the IL-17 (interleukin-17) signaling pathway, an inflammatory mediator produced by T cells and other immune cells, which affects the progression of gouty arthritis by promoting inflammation and promoting the production of inflammatory factors [30], Downregulated lncRNA-regulated mRNA is enriched in Salmonella infection, colorectal cancer and other pathways, these signaling pathways are closely related to the intestinal flora, after Salmonella infection, the diversity and richness of the intestinal flora will decrease, while some pathogenic bacteria such as Enterobacter and Proteus will increase significantly, these changes will affect the production and release of metabolites of the intestinal flora [31], which in turn has an impact on the intestinal mucosal barrier and the immune system, and may induce inflammatory reactions and abnormal immune responses [32]. In recent years, the relationship between intestinal flora and gout has become a research hotspot, and studies have found that the intestinal flora of gout patients is significantly different from that of normal people [33], the abundance of some flora is related to the occurrence and severity of gout, and the clinical manifestations and metabolic abnormalities of gout can be improved by adjusting the intestinal flora, and the intestinal flora is expected to become a new target for controlling hyperuricemia [34].
In this study, the differential mRNA was analyzed by ROC curve and PPI analysis, and seven genes with high diagnostic value were screened out BTG2, FOS, GATA2, JUN, MAPK6, NAR4, and UTRN, which is a cell growth inhibitor that can inhibit cell proliferation and promote cell differentiation, and inhibit the expression of inflammation-related genes by inhibiting the activity of transcription factors such as NF-κB, STAT3 and MAPK [35]; FOS is a transcription factor that is closely associated with ischemia-reperfusion injury [36], GATA2 is a zinc finger transcription factor that is essential for hematopoiesis and angiogenesis [37], and alterations in the GATA2 gene are associated with the occurrence of familial hyperuricemia [38]; JUN belongs to one of the AP-1 family members, and animal studies conducted by Stephanie B et al. [39] have found that JNK-JUN signaling plays an important role as a pro-death signaling pathway between shrinkage injury and somatic deformation; MAPK6, also known as ERK3 (Extracellular signal-regulated kinase 3), is a member of the MAPK family, uric acid metabolism is the cause of gouty arthritis, but also a common cause of kidney damage, Ho Jae et al. [40] research shows that MAPK-related pathways in gouty kidney injury is of great significance.
NAR4 (nitrate assimilation related 4) is a group of proteins involved in nitrate reduction, involved in processes such as plant growth and development [41], in gout research, the role of NAR protein has not been further studied and needs to be further explored. UTRN, a protein located in the cell membrane, plays an important role in muscle cells, and studies have found that UTRN promotes apoptosis and reduces inflammation.
In the ceRNA network, lncRNA, miRNA and mRNA will interact to participate in and regulate gene expression, lncRNA can adsorb more miRNA, thereby reducing the binding of miRNA to mRNA, lncRNA itself can also interact directly with mRNA, thereby affecting the stability of mRNA, so the upregulation of lncRNA can make the expression level of mRNA up-regulated or down-regulated, In this study, the ceRNA relationship of key module mRNA was predicted, and it was found that FAM182A, UCA1, MIR22HG, TTY10, FAM215B five lncRNAs were adsorbed by adsorbing hsa-miR-27a-3p, hsa-miR-1297, hsa-miR-206, hsa-miR-449c-5p, hsa-miR-139-5p and hsa-miR-217 in turn affect the expression of key mRNAs, which may have important implications in the pathogenesis of gout(see Table 1 for details).