{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:29:24Z","timestamp":1788866964502,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Background<\/jats:title>\n \n Vascular smooth muscle cell (VSMC) senescence is a critical driver of vascular aging and various age-related cardiovascular diseases. Endogenous sulfur dioxide (SO\n 2<\/jats:sub>\n ), a newly identified key cardiovascular gaseous signaling mediator, accelerates collagen deposition and vascular remodeling in VSMCs when downregulated. However, its effects on VSMC senescence remain unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n This study focused on exploring the role of endogenous SO\n 2<\/jats:sub>\n in VSMC senescence and its associated molecular pathways.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Aged mice (24\u00a0months old), VSMC-specific aspartate aminotransferase 1 (AAT1) knockout (VSMC-AAT1-KO) mice, D-galactose (D-gal)-treated aorta rings and rat VSMC line A7r5 were used in the experiments. AAT1 expression was detected by Western blot and single-cell RNA sequencing. Senescence markers Tp53, p21\n Cip\/Waf<\/jats:sup>\n ,\n interleukin 1\u03b2<\/jats:italic>\n (\n IL-1\u03b2<\/jats:italic>\n ) and\n IL6<\/jats:italic>\n expression were detected by Western blot and real-time quantitative PCR. Senescence-associated \u03b2-galactosidase (SA-\u03b2-gal) activity was detected using SA-\u03b2-gal staining kit. Sulphenylation of interferon regulatory factor 1 (IRF1) was detected using a biotin switch assay. The plasmid for mutant IRF1 (mutation of cysteine 83 to serine, C83S) were constructed by site-directed mutagenesis.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The expression of AAT1, a key enzyme for SO\n 2<\/jats:sub>\n production, was reduced in the aortic tissue of aged mice in comparison to young mice. VSMC-AAT1-KO mice exhibited elevated protein expression of senescence markers Tp53, p21\n Cip\/Waf<\/jats:sup>\n and \u03b3-H2AX in the aortic tissue. AAT1 knockdown in VSMCs elevated expression of Tp53, p21\n Cip\/Waf<\/jats:sup>\n ,\n IL-1\u03b2<\/jats:italic>\n and\n IL-6<\/jats:italic>\n , and enhanced SA-\u03b2-gal activity. While SO\n 2<\/jats:sub>\n donor supplementation rescued VSMC senescence caused by AAT1 knockdown and blocked aortic ring aging induced by D-gal. Mechanistically, SO\n 2<\/jats:sub>\n promoted IRF1 sulphenylation, inhibited IRF1 nuclear translocation, which in turn downregulated the expression of senescence markers and the activity of SA-\u03b2-gal. Furthermore, mutation of C83 in IRF1 abolished SO\n 2<\/jats:sub>\n -mediated IRF1 sulphenylation and blocked the inhibitory effect of SO\n 2<\/jats:sub>\n on VSMC senescence.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Reduction of the endogenous SO\n 2<\/jats:sub>\n \/AAT1 pathway played a crucial role in driving VSMC senescence. Endogenous SO\n 2<\/jats:sub>\n counteracted VSMC senescence and vascular aging via the sulphenylation of IRF1 at C83.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2025.1516885","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:27:26Z","timestamp":1743136046000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Vascular smooth muscle cell-derived SO2 sulphenylated interferon regulatory factor 1 to inhibit VSMC senescence"],"prefix":"10.3389","volume":"16","author":[{"given":"Bingquan","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoshu","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/s41569-023-00881-3","article-title":"Hallmarks of cardiovascular ageing","volume":"20","author":"Abdellatif","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.3389\/fimmu.2019.01176","article-title":"Direct inhibition of IRF-dependent transcriptional regulatory mechanisms associated with disease","volume":"10","author":"Antonczyk","year":"2019","journal-title":"Front. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1161\/strokeaha.111.648667","article-title":"Intracranial carotid artery atherosclerosis: prevalence and risk factors in the general population","volume":"43","author":"Bos","year":"2012","journal-title":"Stroke"},{"key":"B4","doi-asserted-by":"publisher","first-page":"eado8860","DOI":"10.1126\/scisignal.ado8860","article-title":"IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages","volume":"18","author":"Chavez","year":"2025","journal-title":"Sci. Signal"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.1042\/cs20170274","article-title":"Sulphur dioxide suppresses inflammatory response by sulphenylating NF-\u03baB p65 at Cys(38) in a rat model of acute lung injury","volume":"131","author":"Chen","year":"2017","journal-title":"Clin. Sci. (Lond)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"101480","DOI":"10.1016\/j.arr.2021.101480","article-title":"Roles and functions of antisense lncRNA in vascular aging","volume":"72","author":"Cui","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1470320318778898","DOI":"10.1177\/1470320318778898","article-title":"Sulfur dioxide improves endothelial dysfunction by downregulating the angiotensin II\/AT(1)R pathway in D-galactose-induced aging rats","volume":"19","author":"Dai","year":"2018","journal-title":"J. Renin Angiotensin Aldosterone Syst."},{"key":"B8","doi-asserted-by":"publisher","first-page":"4688","DOI":"10.7150\/thno.36862","article-title":"Absence of interferon regulatory factor 1 protects against atherosclerosis in apolipoprotein E-deficient mice","volume":"9","author":"Du","year":"2019","journal-title":"Theranostics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trsl.2022.11.001","article-title":"Non-canonical NF-\u03baB contributes to endothelial pyroptosis and atherogenesis dependent on IRF-1","volume":"255","author":"Fan","year":"2023","journal-title":"Transl. Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/nm.2755","article-title":"IgE and mast cells in allergic disease","volume":"18","author":"Galli","year":"2012","journal-title":"Nat. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"101898","DOI":"10.1016\/j.redox.2021.101898","article-title":"Endogenous SO(2)-dependent Smad3 redox modification controls vascular remodeling","volume":"41","author":"Huang","year":"2021","journal-title":"Redox Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1089\/ars.2021.0213","article-title":"Sulfur dioxide: endogenous generation, biological effects, detection, and therapeutic potential","volume":"36","author":"Huang","year":"2022","journal-title":"Antioxid. Redox Signal"},{"key":"B13","doi-asserted-by":"publisher","first-page":"325","DOI":"10.3389\/fimmu.2019.00325","article-title":"Regulating IRFs in IFN driven disease","volume":"10","author":"Jefferies","year":"2019","journal-title":"Front. Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/s41586-024-07693-6","article-title":"Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming","volume":"634","author":"Lavillegrand","year":"2024","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.atherosclerosis.2010.12.037","article-title":"Regulatory effects of sulfur dioxide on the development of atherosclerotic lesions and vascular hydrogen sulfide in atherosclerotic rats","volume":"215","author":"Li","year":"2011","journal-title":"Atherosclerosis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"729728","DOI":"10.3389\/fcell.2021.729728","article-title":"Endogenous SO(2) controls cell apoptosis: the state-of-the-art","volume":"9","author":"Li","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1007\/s12265-023-10377-7","article-title":"Targeting vascular smooth muscle cell senescence: a novel strategy for vascular diseases","volume":"16","author":"Lin","year":"2023","journal-title":"J. Cardiovasc Transl. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"784799","DOI":"10.3389\/fcell.2021.784799","article-title":"Sulphenylation of CypD at cysteine 104: a novel mechanism by which SO(2) inhibits cardiomyocyte apoptosis","volume":"9","author":"Lv","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"6579","DOI":"10.3390\/ijms21186579","article-title":"Targeting molecular mechanism of vascular smooth muscle senescence induced by angiotensin II, A potential therapy via senolytics and senomorphics","volume":"21","author":"Okuno","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/s10557-023-07523-3","article-title":"IL-33 suppresses the progression of atherosclerosis via the ERK1\/2-IRF1-VCAM-1 pathway","volume":"38","author":"Qian","year":"2024","journal-title":"Cardiovasc Drugs Ther."},{"key":"B21","doi-asserted-by":"publisher","first-page":"110386","DOI":"10.1016\/j.virol.2024.110386","article-title":"Role of Interferon Regulatory Factor 1 in acute and chronic virus infections","volume":"603","author":"Rahlf","year":"2025","journal-title":"Virology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e84238","DOI":"10.7554\/eLife.84238","article-title":"Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest","volume":"12","author":"Rossi","year":"2023","journal-title":"Elife"},{"key":"B23","doi-asserted-by":"publisher","first-page":"933","DOI":"10.18632\/aging.202204","article-title":"IRF-1 contributes to the pathological phenotype of VSMCs during atherogenesis by increasing CCL19 transcription","volume":"13","author":"Shen","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1369326","DOI":"10.3389\/fimmu.2024.1369326","article-title":"Sulfur dioxide inhibits mast cell degranulation by sulphenylation of galectin-9 at cysteine 74","volume":"15","author":"Song","year":"2024","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.bbrc.2020.02.040","article-title":"Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation","author":"Song","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1038\/s41580-024-00738-8","article-title":"SenNet recommendations for detecting senescent cells in different tissues","volume":"25","author":"Suryadevara","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"9367673","DOI":"10.1155\/2020\/9367673","article-title":"Endothelin-1 downregulates sulfur dioxide\/aspartate aminotransferase pathway via reactive oxygen species to promote the proliferation and migration of vascular smooth muscle cells","volume":"2020","author":"Tian","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.jacc.2019.11.061","article-title":"Mechanisms of vascular aging, A geroscience perspective: JACC focus seminar","volume":"75","author":"Ungvari","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e67","DOI":"10.1038\/cddis.2010.43","article-title":"Pegylated IFN-\u03b1 sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1 mediated signaling","volume":"1","author":"Upreti","year":"2010","journal-title":"Cell Death Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1093\/hmg\/ddg018","article-title":"A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia","volume":"12","author":"Wessely","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1161\/atvbaha.121.316883","article-title":"Single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing reveals cellular and molecular dynamics of aortic aging in mice","volume":"42","author":"Xie","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"6874","DOI":"10.3390\/ijms25136874","article-title":"The role of interferon regulatory factors in liver diseases","volume":"25","author":"Zeng","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"910580","DOI":"10.3389\/fcvm.2022.910580","article-title":"Senescence in vascular smooth muscle cells and atherosclerosis","volume":"9","author":"Zha","year":"2022","journal-title":"Front. Cardiovasc Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.freeradbiomed.2025.01.054","article-title":"Sulfur dioxide controls M1 macrophage polarization by sulphenylation of prolyl hydroxylase 2 at cysteine 260","volume":"230","author":"Zhang","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jare.2020.08.017","article-title":"Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation","volume":"29","author":"Zhang","year":"2021","journal-title":"J. Adv. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"103124","DOI":"10.1016\/j.redox.2024.103124","article-title":"Endogenous sulfur dioxide deficiency as a driver of cardiomyocyte senescence through abolishing sulphenylation of STAT3 at cysteine 259","volume":"71","author":"Zhang","year":"2024","journal-title":"Redox Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"701583","DOI":"10.3389\/fcvm.2021.701583","article-title":"SUMOylation as a therapeutic target for myocardial infarction","volume":"8","author":"Zhao","year":"2021","journal-title":"Front. Cardiovasc Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1097\/fjc.0000000000000882","article-title":"Sulfur dioxide: an endogenous protector against myocardial injury","volume":"76","author":"Zhou","year":"2020","journal-title":"J. Cardiovasc Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.14670\/hh-29.1107","article-title":"Effect of endogenous sulfur dioxide in regulating cardiovascular oxidative stress","volume":"29","author":"Zhu","year":"2014","journal-title":"Histol. Histopathol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/j.bbrc.2020.02.013","article-title":"Macrophage-derived sulfur dioxide is a novel inflammation regulator","volume":"524","author":"Zhu","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"84","DOI":"10.14336\/ad.2022.0711","article-title":"Lysine malonylation and its links to metabolism and diseases","volume":"14","author":"Zou","year":"2023","journal-title":"Aging Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.ejphar.2017.11.005","article-title":"SIRT5 and post-translational protein modifications: a potential therapeutic target for myocardial ischemia-reperfusion injury with regard to mitochondrial dynamics and oxidative metabolism","volume":"818","author":"Zou","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1161\/circresaha.109.215483","article-title":"SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells","volume":"106","author":"Zu","year":"2010","journal-title":"Circ. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1516885\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:27:29Z","timestamp":1743136049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1516885\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":43,"alternative-id":["10.3389\/fphar.2025.1516885"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1516885","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]},"article-number":"1516885"}}