Access the full text.
Sign up today, get DeepDyve free for 14 days.
Background Sirtuin 1 (SIRT1) is reported downregulated in rheumatoid arthritis (RA), and the protective effects of SIRT1 on tissue damage and organ failure may be related to cellular ferroptosis. However, the exact mechanism by which SIRT1 regulates RA remains unclear. Methods Quantitative real-time PCR (qPCR) and western blot assays were performed to explore the expressions of SIRT1 and Yin Yang 1 (YY1). CCK-8 assay was used for cytoactive detection. The interaction between SIRT1 and YY1 was validated by dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). DCFH-DA assay and iron assay were applied to detect the reactive oxygen species (ROS) and iron ion levels. Results In the serum of RA patients, SIRT1 was downregulated, but YY1 was upregulated. In LPS-induced synovio- cytes, SIRT1 could increase cell viability and decrease ROS and iron levels. Mechanistically, YY1 downregulated the expression of SIRT1 by inhibiting its transcription. YY1 overexpression partly revised the effects of SIRT1 on ferroptosis in synoviocytes. Conclusion SIRT1 is transcriptionally repressed by YY1 and inhibits the ferroptosis of synoviocytes induced by LPS, so as to relieve the pathological process of RA. Therefore, SIRT1 might be a new diagnosis and therapeutic target of RA. Highlights 1. Combining SIRT1 with synoviocytes ferroptosis in rheumatoid arthritis for the first time. 2. The transcription factor YY1 combined to the SIRT1 promoter in synovial cells and inhibited its expression and functional roles. 3. The inhibition of SIRT1 with YY1 decreased the ferroptosis in synoviocytes. Keywords Rheumatoid arthritis, Ferroptosis, SIRT1, YY1 Yuwei Zhan and Zhou Yang are co-first author. *Correspondence: Shudian Lin LinSD1983@163.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Zhan et al. Advances in Rheumatology (2023) 63:9 Page 2 of 11 synovial cells in RA in vitro, increasing the understand- Introduction ing of RA pathogenesis. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the erosion of adja- cent cartilage and bone caused by chronic joint inflam - Methods mation. Approximately 0.5–1% of adults in China suffer Clinical sample collection from RA, placing a heavy burden on economy and health Serum samples from healthy volunteers (female 9 and . Researches indicated that the main causes of RA are male 11, average age 42.7 ± 6.3 year) and RA patients genetic and environmental factors [2, 3]. However, the (female 12 and male 8, average age 47.5 ± 5.6 year) who exact mechanism of the pathogenesis and progression received joint replacement of the knee joint were col- of RA remains unknown. Synovitis is recognized as the lected in the Hainan General Hospital (20 samples for major characteristic of RA . The normal synovium is each group). All RA patients fulfilled the American Col - mainly composed of fibroblast-like synoviocytes, which is lege of Rheumatology criteria for classification of disease the nutrient provider of articular cartilage and the pro- . The healthy control specimens were from patients tector of joint structures or adjacent tissues . In RA, with joint trauma undergoing joint replacement surgery, the number of synoviocytes conspicuously increased and who were free from autoimmune or inflammatory dis - could cause joint destruction by producing proinflamma - eases. Participants signed the informed consent forms tory cytokines . Therefore, it is of great significance to and the Ethics Committee of Hainan General Hospital find an effective therapeutic agent for synovitis and clar - approved the procotol (approval number: 2012233). ify its mechanism of action for the treatment of RA. Lipid peroxidation and reactive oxygen species (ROS) were necessary in synovitis development , which have Cell culture and treatment been proved contributing to the progressive disease Synoviocytes (HUM-CELL-0060, Wuhan PriCells Bio- course. Ferroptosis is a new kind of non-apoptotic and medical Technology, China) were cultured in Dulbec- iron-dependent cell death, which is featured by iron accu- co’s modified Eagle’s medium (DMEM; HyClone, South mulation and lipid peroxidation to produce ROS result- Logan, UT, USA) supplemented with 10% heat-inacti- ing in cell death . Some recent findings have indicated vated fetal bovine serum (FBS, GIBCO, Grand Island, NY, that ferroptosis may also be related to the occurrence and USA), 100 U/mL penicillin, and 100 μg/mL streptomycin development of inflammatory arthritis, including RA . (HyClone) and were incubated in a 5% C O incubator at Enhanced lipid peroxidation and decreased glutathione 37 °C. For RA cell model treatment, synoviocytes were peroxidase (GPX, an anti-oxidant agent) were found in treated with 1 µg/mL lipopolysaccharide (LPS; Sigma- synoviocytes from patients with RA [9, 10]. Abnormal Aldrich, St. Louis, MO, USA) for 24 h. iron metabolism is another contributor of ferroptosis and iron deposits were determined in RA [11, 12]. Moreover, Cell transfection ferroptosis is a crucial process for synovium injury in RA The full-length cDNA of YY1 and SIRT1 was amplified and regulation in the ferroptosis of synovial cells is ben- and integrated into the pcDNA-3.1 expression vector eficial to RA treatment . (Invitrogen, Carlsbad, CA, USA). Cell transfection was Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleo- carried out according to the standard protocol using tide-dependent protein deacetylases, manages the key Lipofectamine 3000 (Invitrogen). After 48 h, the cells part of lipid metabolism . It was reported that SIRT1 were used for subsequent experiments. expressed decreasingly in RA synovial vessels . Our previous study proved that SIRT1 overexpression pos- sessed anti-RA activity . Furthermore, the activation Cell counting kit‑8 (CCK‑8) assay of SIRT1 can restrain excess iron-induced ferroptosis The cell viability was assessed by a CCK-8 assay (Beyo - evidenced by decrease of lipid ROS levels and increase time, Jiangsu, China). The cells were seeded into a 96-well GPX4 expression . Additionally, the ablation of intes- plate and then cultured at 37℃ for 48 h. Next, 10 µL of tinal SIRT1 ameliorated dysfunctional iron metabolism, CCK-8 reagent was added, and the cells were incubated increased hepatic glutathione contents, and attenuated at 37℃ for an additional 2 h. The optical density (OD) of lipid peroxidation . However, in the progression the solution was then measured at 450 nm to assess cell of RA, the regulation of SIRT1 in ferroptosis remains viability. unclear. Based on these previous studies, we aimed to inves- tigate whether SIRT1 could regulate the ferroptosis of Zhan et al. Advances in Rheumatology (2023) 63:9 Page 3 of 11 Glutathione (GSH)/oxidized GSH (GSSG) detection Western blot Anticoagulant treated blood samples were centrifuged The cells were collected and lysed in RIPA buffer (Beyo - at 1000 × g for 10 min at 4 °C. Then, the top plasma time) to extract total proteins. Equal amounts of protein layer was transferred to a new tube, followed by addi- (30 µg) were separated on a 10% SDS-PAGE gel, and then tion with 1/4 vol of 5% SSA. The samples were added in transferred to a PVDF membrane (Invitrogen). The mem - a 96-well plate and GSH/GSSG ratio was detected using brane was blocked with 5% skim milk powder in tris- a GSH/GSSG Detection Assay kit (#ab138881; Abcam, buffered saline tween (TBST). The membrane was then Cambridge, MA, USA), following the manufacturer’s incubated overnight at 4℃ with the following primary protocols. antibodies: SIRT1 (#ab110304, Abcam), YY1 (#ab227269, Abcam). Next, the membrane was washed 3 times in Iron level measurement TBST for 5 min each and then incubated with HRP-con- 2+ The intracellular ferrous iron level (Fe ) were detected jugated secondary antibody for 2 h at room temperature. using the iron assay kit (#ab83366, Abcam). Synoviocytes After washing, the protein bands were analyzed by an seeded in 24-well plate were washed with cold PBS twice ECL detection kit (Beyotime). and then lysed with cell lysis buffer for 2 h, followed by addition with the iron reducer into the collected super- Dual‑luciferase reporter assay natants. Finally, iron probe was added for 1 h, and the Synoviocytes were seeded into a 24-well plate, and the content was immediately measured on a colorimetric cell density had increased to 60–70% per well on the microplate reader (OD 593 nm). second day. Two groups were set up as pcDNA3.1 and pcDNA-YY1 (dual-luciferase reporter plasmid was pur- Detection of ROS level chased from HonorGene, China). After 48 h, luciferase After relevant stimulation and/or treatment, cells were activity was detected by a dual-luciferase reporter kit cultivated in a 24-well plate at 37 °C in serum-free (Promega, Madison, WI, USA) and expressed as relative medium for 6 h. Cells were then rinsed using PBS and activity. stained with 10 μM DCFH-DA (Sigma-Aldrich) for 20 min in dark. Finally, these cells were washed with PBS Chromatin immunoprecipitation (ChIP) assay and the fluorescence was observed with a confocal laser The binding of YY1 to the SIRT1 promoter was examined scanning microscope. using ChIP assay with pierce magnetic ChIP kit (Thermo Fisher Scientific), according to the manufacturer’s proto - RNA extraction and quantitative real‑time (qPCR) col. Cells were fixed with formaldehyde (1%) for 10 min TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, at room temperature. YY1 antibody (#ab227269, Abcam) USA) was used to obtain total RNA from the synovio- was utilized to generate immunoprecipitants, whereas cytes or clinical samples. A NanoDropTM 2000 spec- an IgG antibody (#sc-69786, Santa Cruz Biotechnology, trophotometer (Thermo Fisher Scientific) was utilized CA, USA) was used as the blank control group. The recu - to assess the RNA quality. The RNA samples were used perated DNA fragments were evaluated via qPCR. The to synthesize cDNA by using a Primescript RT reagent relative level of SIRT1 promoter was normalized to the kit (Takara, Dalian, China). qPCR was then performed average level of the IgG group. according to the directions of the SYBRTM Green mas- ter mix (TaKaRa, Tokyo, Japan). The primers used in this Statistical analysis study were listed in Table 1. Statistical analysis was performed with SPSS 22.0 soft- ware and GraphPad Prism 8.0. The data were expressed as the mean ± SD and assessed normality by Shapiro– Wilk test, followed by analyzed homogeneity of variance utilizing Bartlett’s test. After analysis, all the data were Table 1 Primer sequences for qPCR consistent with normal distribution and homogeneity of Primer name (5’‑3’) Primer sequences variance. Then, the unpaired student’s t-test was used for statistical analysis between two groups, and one-way YY1-Forward 5′-TAC CTG GCA TTG ACC TCT C-3′ analysis of variance followed by Tukey’s test was used YY1-Reverse 5′-GGC CGA GTT ATC CCTGA-3′ for comparison between multiple groups of data. The SIRT1-Forward 5′-TAG ACA CGC TGG AAC AGG TTGC‐3′ correlations were analyzed using Pearson’s correlation SIRT1-Reverse 5′-CTC CTC GTA CAG CTT CAC AGTC‐3′ coefficients. P < 0.05 was defined as indicating statistical GAPDH-Forward 5′-CTC CTC CAC CTT TGA CGC T‐3′ significance. GAPDH-Reverse 5′-GGG TCT CTC TCT TCC TCT TGTG‐3′ Zhan et al. Advances in Rheumatology (2023) 63:9 Page 4 of 11 Fig. 1 RA was associated with ferroptosis and the differential expressions of YY1 and SIRT1. A GSH/GSSG in the serum of healthy volunteers and RA patients were examined by GSH/GSSG assay. B Iron levels in the serum of healthy volunteers and RA patients were examined by iron assay. C SIRT1 expression in the serum of healthy volunteers and RA patients was examined by qPCR. D YY1 expression in the serum of healthy volunteers and RA patients was examined by qPCR. E, F The correlation between SIRT1 and GSH/GSSG, iron level in RA. G, H The correlation between YY1 and GSH/ GSSG, iron level in RA. I The correlation between YY1 and SIRT1 in RA. N = 20, mean ± SD, ***p < 0.001 Results expression was negatively correlated with GSH/GSSG RA was associated with ferroptosis and the differential level (Fig. 1G) and positively correlated with iron level expressions of YY1 and SIRT1 (Fig. 1H). Overall, the ferroptosis may be involved in the We collected 20 clinical blood samples from healthy pathogenetic process of RA and the SIRT1 could be the volunteers and patients with RA. Compared with the crucial molecule in regulating ferroptosis. healthy group, the serum GSH/GSSG level in RA group was significantly decreased (Fig. 1A). However, the serum The effects of LPS on ferroptosis, SIRT1 and YY1 iron content of the RA group increased significantly expressions in synoviocytes (Fig. 1B). Additionally, qPCR was performed to confirm In order to simulate RA in vitro model, we used LPS to SIRT1 and YY1 expression in RA patients. Serum SIRT1 induce synovial cells and explore the occurrence of fer- was found to be downregulated in RA patients (Fig. 1C), roptosis. Compared with the control group, cell viability and YY1 was upregulated (Fig. 1D). Furthermore, SIRT1 of synovial cells induced by LPS was significantly reduced expression was positively correlated with the level of (Fig. 2A). ROS accumulation was related to ferropto- GSH/GSSG (Fig. 1E) and negatively correlated with iron sis, and LPS treatment significantly increased cellular level (Fig. 1F) or YY1 expression (Fig. 1I) in RA. YY1 ROS levels (Fig. 2B). Iron content can directly reflect the Zhan et al. Advances in Rheumatology (2023) 63:9 Page 5 of 11 Fig. 2 SIRT1 was downregulated while ferroptosis and YY1 was upregulated in LPS-induced synoviocytes. A CCK-8 assay assessed viability. B ROS production was detected by DCFH-DA fluorescent probe. C Iron level in the synoviocytes was examined by iron assay kit. D The mRNA expressions of YY1 and SIRT1 in the synoviocytes were examined by qPCR. E The protein levels of YY1 and SIRT1 were detected by western blot. Experiments were carried out in triplicate, mean ± SD, **p < 0.01; ***p < 0.001 Zhan et al. Advances in Rheumatology (2023) 63:9 Page 6 of 11 Overexpression of SIRT1 inhibited LPS‑induced ferroptosis ferroptosis in cells. As expected, the iron content in the in synovial cells LPS induced cells was increased significantly (Fig. 2C). To explore the effect of SIRT1 on synovial cell function, Additionally, SIRT1 mRNA level was found to be down- we overexpressed SITR1 in synovial cells by transfecting regulated, and YY1 mRNA level was upregulated in LPS with recombinant pcDNA3.1 plasmid. Compared with induced synoviocytes (Fig. 2D). Meanwhile, the protein the control group, after LPS induction, the expression of level of SIRT1 in synoviocytes induced by LPS was signif- SIRT1 was significantly downregulated; while transfec - icantly reduced, and the protein level of YY1 was signifi - tion of pcDNA-SIRT1 significantly increased its mRNA cantly increased (Fig. 2E). Therefore, these results were and protein levels (Fig. 3A–B), suggesting the SIRT1 consistent with the clinical level which the ferroptosis overexpression vector has been successfully transfected might be the key to RA. into synovial cells. The CCK-8 assay showed that the cytoactive in the LPS group was significantly reduced Fig. 3 Overexpression of SIRT1 inhibited LPS-induced ferroptosis of synovial cells. Synoviocytes were transfected with pcDNA-3.1 or pcDNA-SIRT1. A The mRNA expression of SIRT1 was examined by qPCR. B The protein level of SIRT1 was examined by western blot. C Cell viability was assessed by CCK-8 assay. D ROS level was detected by DCFH-DA fluorescent probe. E Iron level in the synoviocytes was examined by iron assay kit. Experiments were carried out in triplicate, mean ± SD, **p < 0.01; ***p < 0.001 Zhan et al. Advances in Rheumatology (2023) 63:9 Page 7 of 11 compared with the control group. However, overex- detection confirmed that after overexpression of YY1, pression of SIRT1 significantly increased cell viability the mRNA and protein levels of YY1 were increased, (Fig. 3C). Furthermore, LPS significantly increased cellu - while the expression of SIRT1 was decreased (Fig. 4D–E). lar ROS levels, and overexpression of SIRT1 significantly Taken together, these findings indicated that the decrease reduced ROS production (Fig. 3D). Compared with the in SIRT1 expression could be attributed to the to the control group, the iron content in LPS group was sig- transcriptional repression of YY1. nificantly increased, while overexpression of SIRT1 sig - nificantly reduced the iron content (Fig. 3E). The above YY1/SIRT1 axis promoted the ferroptosis of LPS induced results indicated that overexpression of SIRT1 could synoviocytes inhibit LPS-induced ferroptosis in synovial cells. To further verify the function of YY1 in SIRT1’s effects on LPS-induced synovial cells, we conducted rescue YY1 downregulated the expression of SIRT1 by inhibiting experiments in this section. Firstly, human synovial cells its transcription were transfected with SIRT1 and YY1 overexpression Studies have revealed that the differential expression of plasmids before LPS induction, and cell viability was genes may be regulated by transcription factors [19, 20]. detected by CCK-8. SIRT1 overexpression significantly Accordingly, we suspected that the low expression of enhanced the cytoactive restrained by LPS, while over- SIRT1 in RA may be related to transcriptional regulation. expression of YY1 partly reversed this effect (Fig. 5A). In Therefore, we searched the JASPAR database and found addition, overexpression of SIRT1 significantly reduced that there was a potential binding site between YY1 and LPS-induced cellular ROS production, but overexpres- SIRT1 promoter region (Fig. 4A). ChIP assay detected a sion of YY1 partially abolished with this change (Fig. 5B). high affinity for the binding of YY1 to the promoter of Similarly, overexpression of SIRT1 reduced the iron con- SIRT1 (Fig. 4B). The dual-luciferase reporter assay indi - tent induced by LPS, while overexpression of YY1 sig- cated that compared with the pcDNA3.1 group, over- nificantly increased the iron content (Fig. 5C). The above expression of YY1 significantly reduced the luciferase results demonstrated that YY1 inhibited SIRT1 by tran- activity of the wild type but had no significant effect on scription repression and increased the ferroptosis of syn- the mutant type (Fig. 4C). The qPCR and western blot ovial cells induced by LPS. Fig. 4 YY1 downregulated the expression of SIRT1 by inhibiting its transcription. Synoviocytes were transfected with pcDNA-3.1 or pcDNA-SIRT1. A JASPAR software predicted the potential binding site between YY1 and SIRT1. B ChIP detected the interaction between YY1 and SIRT1. C Dual-luciferase reporter assay detected the combination of YY1 and SIRT1. D The mRNA expression of SIRT1 was examined by qPCR. E The protein level of SIRT1 was examined by western blot. Experiments were carried out in triplicate, mean ± SD, **p < 0.01; ***p < 0.001 Zhan et al. Advances in Rheumatology (2023) 63:9 Page 8 of 11 Fig. 5 YY1 promoted LPS-induced ferroptosis of synoviocytes through transcriptional inhibition of SIRT1. Synoviocytes were transfected with pcDNA-3.1, pcDNA-SIRT1 or pcDNA-YY1. A Cell viability was assessed by CCK-8 assay. B ROS production was detected by DCFH-DA fluorescent probe. C Iron level in the synoviocytes was examined by iron assay kit. Experiments were carried out in triplicate, mean ± SD, ***p < 0.001 ischemia/reperfusion injury , renal cell carcinoma Discussion , cerebral infarction  and so on. Moreover, ROS Ferroptosis is an iron-dependent form of nonapoptotic accompanied with ferroptosis may function as a recipro- cell death firstly discovered by Dixon and colleagues in cal with cell death that interplays with RA . Exces- 2012 . In recent years, research of ferroptosis con- sive accumulation of ROS could damage numerous cell tinuously emerging in various disease. Ferroptosis is types, which is related to the decrease of GSH content considered to be an important factor in myocardial Zhan et al. Advances in Rheumatology (2023) 63:9 Page 9 of 11 . Lower GSH levels and GSH to oxidized GSH ratio cell pathogenicity by interaction with T-bet in RA . (GSH/GSSG), as measures of redox balance, have previ- Wang et al. demonstrated that lncRNA NEAT1 targets ously been reported in the cells for survival inhibition fibroblast-like synoviocytes in RA via the miR-410-3p/ and ferroptosis . In our research, the lower GSH/ YY1 axis . Inhibition of YY1 reduced the neutrophil GSSG and higher iron content were detected in serum infiltration by inhibiting IL-8 production via the PI3K- samples from RA patients, which reflected that the fer - Akt-mTOR signaling pathway in RA . In the pre- roptosis in RA patients were enhanced. Meanwhile, sent study, YY1 was verified to have a high affinity for SIRT1 was found to be downregulated in RA patients, binding to SIRT1 promoter region. YY1 downregulates and YY1 was upregulated. Further correlation analysis the expression of SIRT1 by inhibiting its transcription, showed that YY1 was positively correlated with ferropto- thereby prompting the ferroptosis of LPS induced synovi- sis, and SIRT1 was negatively correlated with ferroptosis. ocytes. Therefore, YY1 can be a novel therapeutic target In our previous study, we confirmed that SITR1 overex - for treatment of RA. pression restrained the proliferation and inflammation of Furthermore, there are also some other limitations in RA-fibroblast-like synoviocytes . Hussain et al. also this study: (i) iron chelations were not used for further demonstrated that significant downregulation of mito - validation on the present results; (ii) the regulatory effect chondrial SIRT1 was related with increased risk of arthri- of SIRT1 on ferroptosis was not verified in RA animal tis and can be used as an indicator of clinical prognosis models; (iii) it is unclear whether there is a significant . However, the underlying mechanisms of the action difference in the relevant indicators between the serum of SIRT1 in RA need deeper investigation. samples from RA patients undergoing joint replacement Although the functions of human sirtuins have not and RA patients without joint replacement. These would yet been determined, Pasquereau et al. found that the be the research directions in our future studies. increased inflammation in adjuvant-induced arthritis rats compared to healthy control was accompanied by an increased SIRT1 activity in both PBMCs and liver . Conclusions However, SIRT1 expression in RA endothelial cells and In this study, we firstly revealed the functional role and synovial vessels was declined. Conditional SIRT1 dele- mechanism of SIRT1 in regulating ferroptosis during tion in endothelial cells delayed the dissolution of experi- RA progression. Overall, SIRT1 is transcriptionally sup- mental methyl-bovine serum albumin-(mBSA)-induced pressed by YY1 and modulates the ferroptosis of syno- arthritis . Additionally, SIRT1 was found to be down- vial cells induced by LPS. These research findings would regulated in RA patients and LPS-induced synovial cells. provide reliable theoretical support for further under- Li et al. revealed that SIRT1 restrained the invasive and standing the pathogenesis of RA and developing new inflammatory responses of RA-fibroblast-like synovio - treatment strategies. cytes by inhibiting the NF-κB pathway . In addition, upregulation of SIRT1 induced by resveratrol in RA- Abbreviations fibroblast-like synoviocytes may significantly reverse the RA Rheumatoid arthritis invasion of these cells and attenuate joint inflammation SIRT1 Sirtuin 1 YY1 Yin Yang 1 . Luo et al. found that the inhibition of ferroptosis by ChIP Chromatin immunoprecipitation activating the GPX4 pathway may be exploited as a new ROS Reactive oxygen species therapeutic strategy for RA . In this study, the over-LPS Lipopolysaccharide qPCR Quantitative real-time PCR expression of SIRT1 inhibited LPS-induced ferroptosis of GPX4 Glutathione peroxidase 4 synoviocytes presenting as reduced ROS production and CCK-8 Cell counting kit-8 iron ion level. u Th s, synoviocyte ferroptosis might be a GSH Glutathione GSSG Oxidized GSH new target of SIRT1 in RA. TBST Tris-buffered saline tween YY1 is a widely distributed transcription factor belong- ing to Gli-Kruppel zinc finger proteins and is involved in Acknowledgements We would like to thank the anonymous reviewers who have helped to the inhibition and activation of various gene promoters. improve the paper. YY1 can activate or repress gene promoters by direct- ing histone deacetylases and histone acetyltransferases Author contributions SL guaranteed the integrity of the entire study; YZ designed the study and to the promoter. Therefore, histone modification may literature research; ZY defined the intellectual content; FZ performed experi- also be closely related to YY1. Lin et al. demonstrated ment; YH collected the data; Shudian Lin analyzed the data; SL wrote the main that the regulation of YY1 by miR-124-3p facilitate Th17 manuscript and prepared figures. All authors reviewed the manuscript. All authors read and approved by the final manuscript. Zhan et al. Advances in Rheumatology (2023) 63:9 Page 10 of 11 Funding 11. Bennett RM, Williams ED, Lewis SM, Holt PJ. Synovial iron deposition in This work was supported by Hainan Provincial Natural Science Foundation of rheumatoid arthritis. Arthritis Rheum. 1973;16(3):298–304. China (820MS128), and project supported by Hainan Province Clinical Medical 12. Luo H, Zhang R. Icariin enhances cell survival in lipopolysaccharide- Center (2021276). induced synoviocytes by suppressing ferroptosis via the Xc-/GPX4 axis. Exp Ther Med. 2021;21(1):72. Availability of data and materials 13. Hong T, Ge Z, Zhang B, Meng R, Zhu D, Bi Y. Erythropoietin suppresses The datasets used or analyzed during the current study are available from the hepatic steatosis and obesity by inhibiting endoplasmic reticulum corresponding author on reasonable request. stress and upregulating fibroblast growth factor 21. Int J Mol Med. 2019;44(2):469–547. Code availability 14. Leblond A, Pezet S, Cauvet A, Casas C, Pires Da Silva J, Herve R, et al. Not applicable. Implication of the deacetylase sirtuin-1 on synovial angiogenesis and persistence of experimental arthritis. Ann Rheum Dis. 2020; 79(7):891–900 15. Yang Z, Lin SD, Zhan F, Liu Y, Zhan YW. LncRNA GAS5 alleviates rheuma- Declarations toid arthritis through regulating miR-222-3p/Sirt1 signalling axis. Autoim- munity. 2021;54(1):13–22. Ethics approval and consent to participate 16. Su G, Yang W, Wang S, Geng C, Guan X. SIRT1-autophagy axis inhibits Participants signed the informed consent forms and the Ethics Committee of excess iron-induced ferroptosis of foam cells and subsequently increases Hainan General Hospital approved the procotol (approval number: 2021233). IL-1Beta and IL-18. Biochem Biophys Res Commun. 2021;561:33–9. 17. Zhou Z, Ye TJ, DeCaro E, Buehler B, Stahl Z, Bonavita G, et al. Intestinal Consent for publication SIRT1 deficiency protects mice from ethanol-induced liver injury by Not Applicable. mitigating ferroptosis. Am J Pathol. 2020;190(1):82–92. 18. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. Competing interests The American rheumatism association 1987 revised criteria for the clas- The authors declare that they have no known competing financial interests sification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. or personal relationships that could have appeared to influence the work 19. Qiao K, Ning S, Wan L, Wu H, Wang Q, Zhang X, et al. LINC00673 is reported in this paper. activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway. J Exp Clin Cancer Res. Author details 2019;38(1):418. Department of Rheumatology, Hainan General Hospital, Hainan Affiliated 20. Chen HY, Xiao ZZ, Ling X, Xu RN, Zhu P, Zheng SY. ELAVL1 is transcrip- Hospital of Hainan Medical University, No.19 Xiuhua Road, Xiuying District, tionally activated by FOXC1 and promotes ferroptosis in myocardial Haikou 570311, Hainan, China. ischemia/reperfusion injury by regulating autophagy. Mol Med. 2021;27(1):14. Received: 20 July 2022 Accepted: 24 February 2023 21. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. 22. Lu H, Xiao H, Dai M, Xue Y, Zhao R. Britanin relieves ferroptosis-mediated myocardial ischaemia/reperfusion damage by upregulating GPX4 References through activation of AMPK/GSK3beta/Nrf2 signalling. Pharm Biol. 1. Wang J, Yu L, Deng J, Gao X, Chen Y, et al. Short-term effect of meteoro - 2022;60(1):38–45. logical factors on the risk of rheumatoid arthritis hospital admissions: a 23. Yangyun W, Guowei S, Shufen S, Jie Y, Rui Y, Yu R. Everolimus acceler- distributed lag non-linear analysis in Hefei. China Environ Res. 2021;207: ates Erastin and RSL3-induced ferroptosis in renal cell carcinoma. Gene. 2022;809: 145992. 2. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. 24. Hui Z, Wang S, Li J, Wang J, Zhang Z. Compound Tongluo Decoction Genetic and environmental risk factors for rheumatoid arthritis. Best Pract inhibits endoplasmic reticulum stress-induced ferroptosis and promoted Res Clin Rheumatol. 2017;31(1):3–18. angiogenesis by activating the Sonic Hedgehog pathway in cerebral 3. Radu AF, Bungau SG. Management of rheumatoid arthritis: an overview. infarction. J Ethnopharmacol. 2022;283: 114634. Cells. 2021;10(11):2587. 25. Xie Z, Hou H, Luo D, An R, Zhao Y, Qiu C. ROS-dependent lipid per- 4. Wu Z, Ma D, Yang H, Gao J, Zhang G, Xu K, et al. Fibroblast-like syn- oxidation and reliant antioxidant ferroptosis-suppressor-protein 1 in oviocytes in rheumatoid arthritis: surface markers and phenotypes. Int rheumatoid arthritis: a covert clue for potential therapy. Inflammation. Immunopharmacol. 2021;93: 107392. 2021;44(1):35–47. 5. Zhang Z, Chen X, Gao B, Sun G, Wang Y, Wang J, et al. PLD1 knockdown 26. Lee H, Ki J, Lee SY, Park JH, Hwang GS. Processed panax ginseng, sun reduces metastasis and inflammation of fibroblast-like synoviocytes in ginseng, decreases oxidative damage induced by tert-butyl hydroperox- rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways. ide via regulation of antioxidant enzyme and anti-apoptotic molecules in Autoimmunity. 2021;54(7):398–405. HepG2 cells. J Ginseng Res. 2012;3:248–55. 6. Chen Z, Zhong H, Wei J, Lin S, Zong Z, Gong F, et al. Inhibition of Nrf2/ 27. Nagasaki T, Schuyler AJ, Zhao J, Samovich SN, Yamada K, Deng Y, et al. HO-1 signaling leads to increased activation of the NLRP3 inflammasome 15LO1 dictates glutathione redox changes in asthmatic airway epithe- in osteoarthritis. Arthritis Res Ther. 2019;21(1):300. lium to worsen type 2 inflammation. J Clin Invest. 2022;132(1): e151685. 7. Verma N, Vinik Y, Saroha A, Nair NU, Ruppin E, Mills G, et al. Synthetic lethal 28. Hussain MZ, Haris MS, Khan MS, Mahjabeen I. Role of mitochondrial combination targeting BET uncovered intrinsic susceptibility of TNBC to sirtuins in rheumatoid arthritis. Biochem Biophys Res Commun. ferroptosis. Sci Adv. 2020; 6(34): 8968 2021;584:60–5. 8. Zhao T, Yang Q, Xi Y, Xie Z, Shen J, Li Z, et al. Ferroptosis in rheumatoid 29. Pasquereau S, Totoson P, Nehme Z, Abbas W, Kumar A, Verhoeven F, et al. arthritis: a potential therapeutic strategy. Front Immunol. 2022;13: Impact of glucocorticoids on systemic sirtuin 1 expression and activity in rats with adjuvant-induced arthritis. Epigenetics. 2021;16(2):132–43. 9. Grönwall C, Amara K, Hardt U, Krishnamurthy A, Steen J, Engström M, 30. Li G, Xia Z, Liu Y, Meng F, Wu X, Fang Y, et al. SIRT1 inhibits rheuma- et al. Autoreactivity to malondialdehyde-modifications in rheumatoid toid arthritis fibroblast-like synoviocyte aggressiveness and inflam- arthritis is linked to disease activity and synovial pathogenesis. J Autoim- matory response via suppressing NF-kappaB pathway. Biosci Rep. mun. 2017;84:29–45. 2018;38(3):BSR20180541. 10. Surapneni KM, Chandrasada Gopan VS. Lipid peroxidation and antioxi- 31. Hao L, Wan Y, Xiao J, Tang Q, Deng H, Chen L. A study of Sirt1 regulation dant status in patients with rheumatoid arthritis. Indian J Clin Biochem. and the effect of resveratrol on synoviocyte invasion and associated joint 2008;23(1):41–4. destruction in rheumatoid arthritis. Mol Med Rep. 2017;16(4):5099–106. Zhan et al. Advances in Rheumatology (2023) 63:9 Page 11 of 11 32. Lin J, Tang J, Lin J, He Y, Yu Z, Jiang R, et al. YY1 regulation by miR-124–3p promotes Th17 cell pathogenicity through interaction with T-bet in rheumatoid arthritis. JCI Insight. 2021; 6(22): 22. 33. Wang Y, Hou L, Yuan X, Xu N, Zhao S, Yang L, et al. LncRNA NEAT1 targets fibroblast-like synoviocytes in rheumatoid arthritis via the miR-410-3p/ YY1 Axis. Front Immunol. 2020;11:1975. 34. Lin J, He Y, Wang B, Xun Z, Chen S, Zeng Z, et al. Blocking of YY1 reduce neutrophil infiltration by inhibiting IL-8 production via the PI3K-Akt- mTOR signaling pathway in rheumatoid arthritis. Clin Exp Immunol. 2019;195(2):226–36. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your ﬁeld rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions
Advances in Rheumatology – Springer Journals
Published: Mar 7, 2023
Keywords: Rheumatoid arthritis; Ferroptosis; SIRT1; YY1
Access the full text.
Sign up today, get DeepDyve free for 14 days.