Long noncoding RNA/circular RNA regulates competitive endogenous RNA networks in rheumatoid arthritis: molecular mechanisms and traditional Chinese medicine therapeutic significances

Abstract Rheumatoid arthritis (RA) is a systemic and autoimmune disease that is mainly featured abnormal fibroblast-like synoviocyte (FLS) proliferation and inflammatory cell infiltration. Abnormal expression or function of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are closely related to human diseases, including RA. There has been increasing evidence showing that in the competitive endogenous RNA (ceRNA) networks, both lncRNA and circRNA are vital in the biological functions of cells. Nevertheless, the exact mechanism of ceRNA in RA remains to be investigated. Herein, we summarized the molecular potencies of lncRNA/circRNA-mediated ceRNA networks in RA, with emphasis on the phenotypic regulation of ceRNA in the progression of RA, including regulation of proliferation, invasion, inflammation and apoptosis, as well as the role of ceRNA in traditional Chinese medicine (TCM) in the treatment of RA. In addition, we also discussed the future direction and potential clinical value of ceRNA in the treatment of RA, which may provide potential reference value for clinical trials of TCM therapy for the treatment of RA. Key messages Long noncoding RNA/circular RNA can work as the competitive endogenous RNA sponge and participate in the pathogenesis of rheumatoid arthritis. Traditional Chinese medicine and its agents have shown potential roles in the prevention and treatment of rheumatoid arthritis via competitive endogenous RNA.


Introduction
Rheumatoid arthritis (RA) is an inflammatory and destructive disease with clinical manifestations of primarily symmetrical polyarthritis and extra-articular injury [1,2].It eventually contributes to joint deformity and disability, seriously reduces the patient's quality of life and affects social participation, which is considered as 'Deathless cancer' [3][4][5][6].The onset of RA has no age limitation with a high incidence, and the age of incidence is mainly 40-60 years, and the number of female RA patients is two to three times of male RA patients [3,7].Currently, the exact pathogenesis of RA remains unknown.This chronic autoimmune disease with a high disability rate, is easy to attack repeatedly and is difficult to cure [8].Meanwhile, the long treatment cycle of this disease brings a huge financial burden to the patient's families and society.The current treatment approaches for RA are based on glucocorticoids, non-steroidal anti-inflammatory drugs, traditional anti-rheumatic drugs, as well as biological agents [9,10].Nevertheless, improper drug administration may cause cardiovascular system damage, liver and kidney dysfunction, gastrointestinal discomfort and other adverse reactions [11].Moreover, the expensive biologic agents weaken the immune system and thus may increase the risk of infections [12].
Fibroblast-like synoviocytes (FLSs) are key effector cells in RA and are regarded as possible therapeutic targets for RA [13,14].FLS is a crucial player in RA pathogenesis, exhibiting diverse invasive features, including apoptosis resistance, hyperproliferation, enhanced invasiveness, as well as secretion of inflammatory mediators [15].On the one hand, RA-FLS can synthesize and secrete matrix metalloproteinases to erode the cartilage, causing inflammatory cell infiltration into the involved joints and chronic cartilage destruction [16].On the other hand, activated FLSs secrete many chemokines, growth factors and proinflammatory cytokines to promote disease severity [17].In addition, the defective apoptosis of FLSs can result in synovial excessive proliferation, pannus formation and progressive joint destruction with irreversible loss of articular function [18].Moreover, oxidative stress exhibits a positive relation with inflammation and promoted joint destruction in RA patients [19,20].It is suggested that the proliferation, invasion, inflammation and apoptosis of RA-FLS are potential mechanisms in RA.
Noncoding RNAs (ncRNAs) account for more than 98% of the human genome and play an important role in gene expression and regulation, including Long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), transcribed pseudogenes [21].miRNAs (20-200 nucleotides) function by binding to complementary sequences in the 3 0 -untranslated region (UTR) of their target mRNAs, thereby triggering translational repression of transcripts or mRNA degradation [22].lncRNAs (more than 200 nucleotides) usually do not encode proteins and act as transcriptional regulators [21].circRNAs are endogenous ncRNAs lacking the 5 0 and 3 0 ends, and their loop-like structure gives them a higher stability [23].The sequence of a pseudogene is usually similar to the corresponding gene, but is at least partially lost, such as not encoding a protein or encoding a protein without function [24].Long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), as well as transcribed pseudogenes, correlate with many diseases, including RA belonging to autoimmune diseases [25][26][27].Although many studies have provided evidence that both lncRNAs and circRNAs become a research hotspot in RA through their functions in many life activities [28,29].However, at the sequence level, lncRNAs and circRNAs are poorly conserved across species.
In 2011, Salmena et al. proposed a competitive endogenous RNA (ceRNA) hypothesis describing that lncRNA/circRNA competes with protein-coding mRNA to bind miRNA [30].It emphasizes that lncRNAs/circRNAs act as miRNA sponges that protect target mRNAs from inhibition by sequestering specific miRNAs [30] (Figure 1).However, due to the limitation of current experimental approaches, this challenging area of ceRNA research is still in its infancy, and there are still many aspects to be improved and some issues to be solved.Fortunately, recent research has shown that ceRNAs participate in several diseases, including cardiovascular and cerebrovascular diseases [31], nervous system diseases [32], respiratory diseases [33], immune system diseases [34,35] and malignant tumours [36,37].
Given the important role of ceRNAs in RA, this review concentrated on the lncRNAs/circRNAsmediated ceRNA networks to figure out the potential functions of lncRNAs/circRNAs in modulating RA.Besides, we systematically summarized the functions of the lncRNA/circRNA-miRNA-mRNA axis in proliferation, invasion, inflammation and apoptosis in different cell lines and traditional Chinese medicine (TCM) intervention effect of ceRNAs in RA treatment (Table 1).Moreover, we probed into the challenges and therapeutic implications of ceRNAs in RA.

lncRNAs and circRNAs as latent diagnostic and prognostic biomarkers
The advancement of high-throughput sequencing and bioinformatics has contributed to the discovery of lncRNAs and circRNAs in RA.Quantities of lncRNAs and circRNAs that are dysregulated in RA cells have been identified, which are utilized as key clinical diagnostic biomarkers in RA.
For example, 5045 differentially expressed lncRNAs were identified via a genome-wide microarray analysis of 10 RA patients and 10 healthy controls, among which 2410 lncRNAs were upregulated and 2635 lncRNAs were downregulated [86].Through transcriptome sequencing (RNA-seq), Long et al. found 341 differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) in three RA patients and normal people [87].Zhang et al. identified 135 lncRNAs differentially expressed in FLSs of RA patients and normal people [88].Of those, ENST00000483588 was upregulated; uc004afb.1,ENST00000438399 and ENST00000452247 were downregulated in RA-FLSs.Receiver operating characteristic (ROC) curve analysis was performed to show that these lncRNAs can act as a suitable biomarker for RA diagnosis.Moreover, microarray analysis was used to identify disease activity-associated 683 upregulated and 1,416 downregulated lncRNAs in PBMCs from RA patients, which showed that ENST00000456270 could be a biomarker of RA risk and severity [89].In another study, Wen et al. analysed the difference between apoptosis-and autophagy-related lncRNAs in PBMCs of three RA patients by high-throughput lncRNA sequencing [90].After biological validation in 20 RA patients and 20 healthy controls, seven lncRNAs (C5orf17, LINC01189, LINC01006, MAPKAPK5-AS1, DSCR9, MIR22HG and ENST00000619282) were validated as the most significantly differentially expressed lncRNAs, which were correlated with clinical indicators and self-cognitive ability of patients [90].
In 2017, a total of 584 circRNAs (255 upregulated and 329 downregulated circRNAs) differentially expressed were observed in RA patients through the circRNA microarray analysis [91].Moreover, the differentially expressed circRNAs in RA were screened and validated by the high-throughput analysis and bioinformatics analyses, underscoring the capacity of hsa_circ_0003353 in immunity and inflammation of RA [92].Through gene microarray technology, Lu et al. obtained 149 upregulated and 250 downregulated circRNAs in PBMCs from RA patients, which showed that lncRNA hsa_circ_101328 has a significant positive correlation with C-reactive protein (CRP) and may be a new marker of RA diagnosis [93].Alternatively, a recent study by Wen et al. found 165 differentially expressed circRNAs via RNA-seq of three RA patients and three healthy controls, further clinical study revealed that hsa circ 0001200, hsa circ 0001566, hsa circ 0003972, as well as hsa circ 0008360 expression levels were in accord with the RNA-seq, which could act as potent biomarkers for RA diagnosis [94].In comparison, 71 dysregulated circRNAs were identified in RA, and both hsa_circ_0000396 and hsa_circ_0130438 may exhibit a better diagnostic value in RA [95].
In general, there are a large number of aberrantly expressed lncRNAs and circRNAs in RA patients in contrast to normal people.In most studies, the number of lncRNAs and circRNAs was closely related to RA disease activity.Due to the variable abundance and interactions and crosstalk of individual ncRNAs, combinatorially variable series of ncRNAs may be more promising as biomarkers than individual ncRNAs.

Regulatory roles of ceRNAs in RA
As the vital regulatory mode of gene expression, the lncRNA/circRNA-mediated ceRNA networks are expected to exhibit pleiotropic effects in autoimmune diseases such as RA.ceRNAs have both beneficial (such as suppressing the malignant subtype of RA-FLS) and detrimental (such as promoting inflammatory responses) roles in RA pathogenesis [51,74].In fact, the lncRNA/circRNAmediated ceRNA network regulates multiple cellular  processes in RA, including proliferation, invasion, inflammation and apoptosis.

Proliferation, migration and invasion capabilities
Like tumour cells, RA-FLSs also share the properties of biological functions and enhanced resistance to apoptosis.Wang et al. found that lncRNA LINC-PINT is upregulated in TNF-a-induced RA-FLSs, which elevates SOCS1 expression through sponging miR-155-5p, leading to the promotion of the proliferation, migration and invasion [38].Another study revealed that Linc0238 exacerbates the tumour-like phenotype of FLSs in RA through the miR-590-5p/MAP2K3 axis [42].
Inhibiting RA-FLS proliferation, migration and invasion are potential therapeutic strategies for RA.Li et al. proposed that the downregulation of circ_ 0130438 ameliorates RA by restricting RA-FLS functional properties via the miR-130a-3p/KLF9 axis [77].

Apoptosis and inflammation
Inflammation and apoptosis are critically important in RA pathogenesis.As described, lncRNA PVT1 was observed to mediate inflammatory responses in RA-FLS by serving as a miR-543 sponge and positively modulating SCUBE2 expression [43].TLR4, as the main receptor impacting the NF-jB activation, could influence RA progression.Yan et al. addressed that via the modulation of the TLR4/miR-6089 axis, lncRNA HIX003209 evoked an inflammatory response in RA [44].Except that, the signalling axis of LINC01197/miR-150/THBS2 [39] and lncRNA CASC2/miR-18a-5p/BTG3 [56] have been elucidated to intensify inflammation and diminish apoptosis of RA-FLS.

Methods for characterization of ceRNA interactions
Several bioinformatic tools and genomics databases can be utilized for the construction of a lncRNA/circRNA-miRNA-mRNA network.Different databases have their own prediction rules and characteristics, which leads to different prediction results, and therefore a combination of various databases is needed to give robust information.
Five main algorithms (TargetScan, RNA22, miRanda, PicTar and PITA) are adopted for the prediction of potential miRNA targets, which is helpful for the miRNA-sponge interactions and ceRNA relationships [99][100][101][102][103].Furthermore, the open-source database StarBase v2.0 (http://starbase.sysu.edu.cn/)provides the CLIP-Seq data to experimentally support the interaction networks of miRNA-mRNA and miRNA-lncRNA [104].This database incorporates the gene expression data (AGO-CLIP and small RNA-seq data), which increases the reliability of the lncRNA/circRNA-miRNA relationship predictions [105].Similarly, many databases can be implemented to probe into the interacting miRNAs of lncRNAs.LncCeRBase is a relatively small database that consists of 432 lncRNA-miRNA-mRNA interactions [106].LncACTdb 2.0 is a comprehensive database that offers comprehensive information on ceRNAs in varying species and diseases [107].
In addition to conducting database predication, the functions of the lncRNA/circRNAs sponging with its target miRNA need to be verified by experiments.First, we need to identify the target lncRNA/circRNA and its functional phenotypes and the clinical diagnostic and prognostic value in diseases.Second, RNA-FISH and nuclear-cytoplasmic separation experiments were chosen to verify whether lncRNA/circRNA mainly located in the cytoplasm, was facilitated to determine whether it can regulate miRNAs at the posttranscriptional level [108].Also exciting is that in cells and tissues, the FISH assay also can evaluate the colocalization of lncRNA/circRNA with miRNAs.But, it is important to note that circRNA is conserved and stable, and formed through back-splicing events of precursor mRNA, which should avoid recognition of their cognate linear RNAs [109].Third, the dual-luciferase reporter gene assay has been widely applied to validate human miRNA targets [110].The luciferase reporter vector wild-type (WT)-lncRNA/circRNA is established by the WT and mutant type (MUT) sequences of lncRNA/circRNA containing the binding sites of miRNA inserting into the pGL3 vector (Promega Corporation) [110].Transfection with miRNA mimics diminished the WT luciferase reporter activity; yet, the transfection failed to diminish the MUT luciferase reporter activity [110].Forth, the co-immunoprecipitation of lncRNA/circRNA and miRNA with anti-AGO2 could suggest that lncRNA/circRNA is observed in RNA-induced silencing complexes containing AGO2, possibly through the interaction with miRNA, which further validates lncRNA/circRNA's miRNA sequestering activity [111].More importantly, direct interaction between lncRNA/circRNA and miRNA was confirmed by luciferase activity and RIP assays, this finding strongly supported the ceRNA theory that lncRNA/circRNA could compete for miRNA [112].Finally, an RNA pull-down assay with biotinylated probes can be designed specifically for the lncRNA/circRNA-miRNA [113].After addressing the RNAs obtained after the enrichment, the interacting miRNA-lncRNA/circRNA molecules are elucidated by mass spectrometry analyses [114].
ceRNA involved in TCM treatment of RA TCM has attracted more and more attention owing to its advantages of safety and fewer adverse reactions [75].The use of herbs in treating RA has a history of thousands of years in many Asian countries, and curative effects have been proven by both clinical applications and experimental research [18,115].As is well known, herbal medicine can function through multiple targets and multiple pathways [116,117].Herb medicine is anti-rheumatic and possesses diverse pharmacological actions, such as regulation of antiinflammatory, analgesic and immunomodulatory, inhibits hyperplasia of synovial cells, and suppresses angiogenesis [118,119].It is still noteworthy that herbal medicines and their monomer show promising effects on the inhibition of synovial hyperplasia, and the specific mechanisms are primarily realized via the regulation of ceRNA.We summarized that TCM exerts its therapeutic effect in RA by regulation of ceRNAs, as detailed in Table 2.
lncRNA/circRNA involved in Chinese medicine monomer treatment of RA Tripterygium wilfordii Hook.f., also called Leigongteng in TCM, is a commonly used anti-rheumatic herbal drug [137].Triptolide (TPL) is a diterpene lactone epoxide compound extracted from Tripterygium, and it possesses diverse biological profiles, such as antifertility, anti-tumour, anti-inflammatory, as well as immunosuppressive activities [138,139].TPL inhibits RA-FLS proliferation, invasion and inflammation by suppressing the levels of TNF-a, IL-1b, IL-6, MMP-3 and MMP-9, exhibiting a therapeutic role in collageninduced arthritis (CIA) rats [129].However, these effects were reversed by lncRNA RP11-83J16.1 overexpression [129].ENST00000619282 expression was elevated both in RA-PBMCs and RA-FLS, while ENST00000619282 was significantly decreased following treatment with TPL [131].In addition, ENST00000619282 showed a close clinical correlation with the disease activity.Furthermore, TPL exerts an anti-inflammatory and pro-apoptotic function that was reversed by overexpression ENST00000619282.The same conclusion could be drawn from another study.TPL exerts anti-inflammatory and anti-migratory effects in RA-FLS through the circRNA 0003353/JAK2/STAT3 signalling pathway [133].
Other Chinese medicine monomers were also reported to exhibit a potential role in treating RA via lncRNAs.For instance, shikonins have been reported to confer an anti-inflammatory role against RA.In a study conducted by Yang et al. shikonin inhibits RA-FLS inflammatory reaction via lncRNA-NR024118 [121].Additionally, it has been found that tanshinone IIA promotes RA-FLS apoptosis by elevating lncRNA GAS5 [128].Moreover, Fang et al. also found that quercetin contributes to induction of RA-FLS apoptosis by upregulating lncRNA MALAT1 [128].
lncRNA/circRNA involved in TCM compound treatment of RA Xinfeng Capsule (XFC) is a TCM prescription that is commonly applied in RA therapy, and which is composed of four TCM components: Radix astragali, Coicis semen, T. wilfordii and Centipedes [140].A recent review demonstrates the effectiveness and safety of XFC for RA therapy via meta-analysis.A multicenter, parallel, placebo-controlled, double-blind and randomized controlled trial (RCT) involving 304 patients with RA from China showed that XFC can effectively reduce joint pain and improve laboratory indicators, which was found to be comparable to leflunomide [141].The level of lncRNA MAPKAPK5-AS1 in the RA-PBMCs and RA-FLS were down-regulated and can mediate RA-FLS inflammation and apoptosis [135].Interestingly, restored lncRNA MAPKAPK5-AS1 can reverse the effect of Xinfeng Capsules (XFC) on RA inflammation and apoptosis, which indicated that lncRNA MK5-AS1 participated in RA treatment with XFC [135].
Huayu Qiangshen Tongbi formula (HQT) is utilized for RA treatment by dissipating blood stasis, activating blood circulation, as well as dispelling pathogenic cold, wind and wet.There has been a study indicating that lncRNA uc.477 has a direct regulatory effect on the expression of miR-19b in RA [120].Importantly, HQT treatment normalized the lncRNA uc.477 and miR-19b levels in RA-FLS and the CIA mice model.Thus, lncRNA uc.477 could be a latent therapeutic marker for HQT on RA and its therapeutic mechanism may be through the upregulation of miR-19b.
ceRNA involved in Chinese medicine monomer treatment of RA Many ceRNA networks were linked to the treatment of T. wilfordii in RA.Zhang et al. suggested that the ceRNA network (lncRNA ENST0000494760/miR-654-5p/C1QC) is confirmed by the results obtained from microarray and was deemed to be a biomarker for RA response to Tripterysium Glycosides Tablets (TGT) by clinical cohort, in vitro and in vivo experiments [123].Circ0003353 was confirmed as a key circRNA that reacted to inflammation and immunity in RA.It was found that circ0003353 sponged miR-31-5p to upregulate CDK1 and thus promote RA-FLS proliferation and inflammation.Interestingly, circ0003353/miR-31-5p/CDK1 axis could reverse the effect of TPL on RA -FLS through a series of rescue and gain-offunction experiments [130].(5 R)-5-hydroxytriptolide (LLDT-8), as a novel analogue of TPL, is both qualified and optimized in structure, and possesses better immunosuppressive activities and lower toxicities than TPL.The LLDT-8-induced elevation of lncRNA WAKMAR2 induced was the most remarkable in RA-FLS and restored WAKMAR2 evoked cell viability, invasion, as well as inflammation in RA-FLS.Mechanistically, it has been proven that WAKMAR2 plays a ceRNA role in regulating E2F1 expression by competitively binding to miR-4478, which can be regulated by LLDT-8 [142].Thus, it is important to consider the ceRNA axis as a potential therapeutic target for T. wilfordii in RA.
Of course, other studies have unveiled the effect of Chinese medicine monomer treatment on RA through the ceRNA axis.For example, In a study conducted by Ma et al. paeoniforin mediated the circ-FAM120A/miR-671-5p/MDM4 pathway to impede RA-FLS viability and inflammation and trigger cell cycle arrest [122].Additionally, one study found that astragaloside regulates the LOC100912373/miR-17-5p/PDK1 axis for the suppressed FLS proliferation in rats with RA [143].Pan et al. also found that total saponins of radix clematis modulated RA-FLS via the OIP5-AS1/miR-410-3p/wnt7b axis [134].Furthermore, arsenic trioxide harbours a protective function on RA-FLS and CIA synovium through blocking the circHIPK3/miR-149-5p/FOXO1/VEGF module [125].Another publication by Duan et al. also elucidated that tetrandrine downregulates NEAT1 expression, mechanistically, NEAT1 exerts 'sponge-like' effects on specific miR-17-5p to affect miR-17-5p binding to target gene STAT3, causing restricted RA-FLS viability and proliferation [144].Thus, the above studies lay a basis for an effective treatment approach for RA.ceRNA involved in TCM compound treatment of RA Huangqin Qingre Chubi Capsule (HQC) is a prescription for RA therapy, which is currently used as an inhospital preparation at the First Affiliated Hospital of Anhui University of Chinese medicine [145].The study on peripheral blood mononuclear cells of 24 patients with RA from China showed that HQC drug-containing serum could activate Adenosine 5 0 -monophosphate (AMP)-activated protein kinase (AMPK) and Forkhead box protein O3a (FoxO3a) proteins in PBMCs of patients with RA and improve the state of oxidative stress in patients with RA [145].Clinical studies have shown that HQC can significantly reduce indicators of disease activity and that it has a good therapeutic effect on decreasing joint pain and improving joint function [146].Circ_0015756 expression was upregulated both in RA-FLS, synovium of CIA mice, as well as CIA-FLS.As reported, circ_0015756 expedited the inflammation and viability of RA by modulating the miR-942-5p/CUL4B/Wnt axis.HQC can attenuate joint damage in CIA mice and inhibit inflammation and proliferation of RA-FLS, which is associated with its interference with the effects of the circ_0015756/miR-942-5p/CUL4B axis [132].The discovery of this axis offers a novel ceRNA mechanism for RA and provides a basis for HQC's functions in RA through multimolecular, multitarget and multi-pathway.

Conclusion and prospects
In the last decade, substantial progress has been made in identifying the genetic basis of RA thanks to the generation of several molecular tools and experimental studies.However, the available clinical therapeutic strategies for RA are still unsatisfactory.ncRNAs are now considered a hot topic of scientific research due to their great potential.Available evidence suggests that ceRNAs can regulate inflammation and autoimmunity.It has been elucidated that lncRNA/circRNA, miRNA and mRNA can play an integral regulatory role in the pathological process of RA in a ceRNA pattern.Specifically, ceRNAs are involved in proliferation, invasion, inflammation and apoptosis phenotypes in RA.Altering lncRNA/circRNA levels to affect target gene levels to reverse RA is promising.In addition, low toxicity and multi-targeted herbal medicines affect ceRNAs at the epigenetic level, which may provide a new reference for the treatment of RA.
Although the role of ceRNAs in RA is becoming increasingly evident, their specific mechanisms in RA progression need to be further explored.Existing studies on the regulation of ceRNA by herbal medicine are still limited to preclinical investigations at the molecular, cellular and animal model levels, which are challenging and promising to translate into clinical practice.Meanwhile, how to ensure therapeutic efficacy and safety, and prevent off-target effects, need to be considered.
In the future, studies on the interactions of ncRNA, ceRNA and RA should lay much attention on the following aspects.Initially, the construction of complex regulatory ceRNA network models with single lncRNA or circRNA modifications in RA is required.Focus on the improvement of the new network model to obtain and develop novel targets or treatment strategies for RA is certainly warranted.Second, in future studies, the sample size must be expanded to improve the reliability of the findings.Third, further validation with in vivo studies is critical for the development of ceRNA-targeted therapy in RA.Forth, in combination with the cells-secreted exosomes or vesicles, the feasibility and safety of RNA-modifying factors wrapped in exosomes is the basis of RA progression.Fifth, it is currently unknown how to effectively control the lncRNA/circRNA levels in target cells.m6A modification was abundant in many circRNAs and lncRNAs, and this kind of methylation modification could drive circRNA and lncRNA translation.Therefore, it is also important to explore the relationship between epigenetic modification and ceRNAs.Finally, TCM is known as multi-compound and multitarget medicines for wide application in RA through multiple targets, pathways, as well as links.UPLC-Q/TOF-MS analysis is a fact and useful technology for identifying TCM complex chemical compounds, which contribute to identifying the main effective ingredient of TCM to exhibit a potential role in treating RA through ceRNA.
In summary, this paper reviews the regulation of RA progression by lncRNA/circRNA-mediated ceRNA patterns involving the regulation of multiple phenotypes of proliferation, migration, apoptosis and inflammation, which provides new avenues for the exploration of autoimmune diseases including RA.Likewise, this review highlights that herbal medicines and their components can treat RA via ceRNAs, pointing to some directions for the clinical application of the aforementioned herbal medicines as anti-RA agents.

Figure 1 .
Figure 1.The concept and types of the competitive endogenous RNAs (ceRNAs).