{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T11:12:36Z","timestamp":1789902756757,"version":"4.0.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cyclosporine A (CsA)-induced nephrotoxicity is a significant cause of chronic kidney disease (CKD), primarily driven by aberrant activation of the NF-\u03baB and TGF-\u03b21 signaling axes. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has established cardioprotective effects, but its potential renoprotective role and underlying mechanisms in CsA-induced CKD remain unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An integrative approach was employed. Network pharmacology identified common targets between vericiguat and CKD. Mendelian randomization (MR) analysis assessed the causal relationship between drug target genes and CKD risk. The therapeutic effects and mechanisms of vericiguat were subsequently validated\n                      <jats:italic>in vivo<\/jats:italic>\n                      using a CsA-induced mouse model and\n                      <jats:italic>in vitro<\/jats:italic>\n                      in human renal tubular epithelial (HK-2) cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Integrated computational analyses pinpointed the NF-\u03baB\/TGF-\u03b21 axis as a core target of vericiguat. In mice, vericiguat treatment dose-dependently ameliorated CsA-induced renal dysfunction, proteinuria, renal inflammation, oxidative stress, and fibrosis. In HK-2 cells, vericiguat suppressed CsA-triggered inflammatory cytokine secretion, fibrotic marker expression, and reactive oxygen species production. Mechanistically, vericiguat inhibited the phosphorylation of the IKK\u03b2\/I\u03baB\u03b1\/NF-\u03baB p65 pathway and the activation of TGF-\u03b21\/Smad signaling, thereby disrupting the inflammation-fibrosis vicious cycle. Genetic manipulation confirmed p65 as a crucial nodal point in this regulatory network.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that vericiguat exerts renoprotective, anti-inflammatory, and anti-fibrotic effects in CsA-induced CKD by modulating the NF-\u03baB\/TGF-\u03b21 axis. These findings provide a novel scientific rationale for drug repurposing of vericiguat and highlight its potential therapeutic value for CKD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1756582","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:39:11Z","timestamp":1769495951000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Vericiguat attenuates cyclosporine A-induced nephropathy by targeting the NF-\u03baB\/TGF-\u03b21 axis: an integrated network pharmacology, Mendelian randomization, and experimental study"],"prefix":"10.3389","volume":"16","author":[{"given":"XuanKe","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MengJie","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaYing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YiJing","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WenXuan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ChunJiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiaoPing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Shihezi University","place":["Shihezi, China"]},{"name":"Department of Nephrology, National Health Commission (NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (Co-construction)","place":["Shihezi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.321748","article-title":"The cardio-kidney patient: epidemiology, clinical characteristics and therapy","volume":"132","author":"Schuett","year":"2023","journal-title":"Circ Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00589-9","article-title":"Chronic kidney disease.","volume":"11","author":"Romagnani","year":"2025","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfad118","article-title":"Hypertension in chronic kidney disease-treatment standard 2023","volume":"38","author":"Georgianos","year":"2023","journal-title":"Nephrol Dial Transpl"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/dci22-0027","article-title":"Diabetes management in chronic kidney disease: A consensus report by the american diabetes association (ADA) and kidney disease: improving global outcomes (KDIGO)","volume":"45","author":"de Boer","year":"2022","journal-title":"Diabetes Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0025-7125(16)30525-9","article-title":"Drug-induced nephropathies","volume":"74","author":"Paller","year":"1990","journal-title":"Med Clin North Am"},{"key":"B6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.2215\/CJN.04800908","article-title":"Calcineurin inhibitor nephrotoxicity","volume":"4","author":"Naesens","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1093\/ejendo\/lvaf182","article-title":"Endocrine effects of long-term calcineurin inhibitor use in solid organ transplant recipients","volume":"193","author":"Diker Cohen","year":"2025","journal-title":"Eur J Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12100999","article-title":"The potential protective effect and underlying mechanisms of physiological unconjugated hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide therapy in a mouse model of cyclosporine A-induced chronic kidney disease","volume":"12","author":"Marghani","year":"2022","journal-title":"Metabolites"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.120259","article-title":"Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt\/\u03b2-catenin and PPAR\u03b3 signaling pathways","volume":"291","author":"Mahmoud","year":"2022","journal-title":"Life Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.2c03577","article-title":"Nontoxic concentration of ochratoxin A aggravates renal fibrosis induced by adriamycin\/cyclosporine A nephropathy via TGF-\u03b21\/SMAD2\/3","volume":"70","author":"Du","year":"2022","journal-title":"J Agric Food Chem"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2020.1729188","article-title":"PPAR \u03b3\/TLR4\/TGF-\u03b21 axis mediates the protection effect of erythropoietin on cyclosporin A-induced chronic nephropathy in rat","volume":"42","author":"Liu","year":"2020","journal-title":"Ren Fail"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915928","article-title":"Vericiguat in patients with heart failure and reduced ejection fraction","volume":"382","author":"Armstrong","year":"2020","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.15922","article-title":"Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial","volume":"324","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-024-01384-1","article-title":"Clinical pharmacokinetic and pharmacodynamic profile of vericiguat","volume":"63","author":"Fritsch","year":"2024","journal-title":"Clin Pharmacokinet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10102471","article-title":"Vericiguat in heart failure: characteristics, scientific evidence and potential clinical applications","volume":"10","author":"Vannuccini","year":"2022","journal-title":"Biomedicines"},{"key":"B16","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1161\/CIRCULATIONAHA.121.052792","article-title":"Evidence-based medical therapy in patients with heart failure with reduced ejection fraction and chronic kidney disease","volume":"145","author":"Beldhuis","year":"2022","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241713226","article-title":"The sGC activator runcaciguat has kidney protective effects and prevents a decline of kidney function in ZSF1 rats","volume":"24","author":"Kraehling","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbad518","article-title":"Network pharmacology: towards the artificial intelligence-based precision traditional Chinese medicine","volume":"25","author":"Zhang","year":"2023","journal-title":"Brief Bioinform"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2021.11.004","article-title":"Network pharmacology: curing causal mechanisms instead of treating symptoms","volume":"43","author":"Nogales","year":"2022","journal-title":"Trends Pharmacol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.04.001","article-title":"Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches","volume":"109","author":"Zuber","year":"2022","journal-title":"Am J Hum Genet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a041302","article-title":"Mendelian randomization","volume":"12","author":"Birney","year":"2022","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115210","article-title":"Identification of bioactive compounds and potential mechanisms of scutellariae radix-coptidis rhizoma in the treatment of atherosclerosis by integrating network pharmacology and experimental validation","volume":"165","author":"Ji","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B23","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1186\/s12903-024-04618-7","article-title":"Based on network pharmacology and molecular docking to explore the potential mechanism of shikonin in periodontitis","volume":"24","author":"Zhao","year":"2024","journal-title":"BMC Oral Health"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-023-10684-w","article-title":"Network pharmacology, molecular docking, and molecular dynamics simulation to elucidate the mechanism of anti-aging action of Tinospora cordifolia","volume":"28","author":"Bisht","year":"2024","journal-title":"Mol Divers"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1285106","article-title":"Exploring causal correlations between inflammatory cytokines and ankylosing spondylitis: a bidirectional mendelian-randomization study","volume":"14","author":"Fang","year":"2023","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1625286","article-title":"Huangkui capsule combined with finerenone attenuates diabetic nephropathy by regulating the JAK2\/STAT3 signaling pathway based on network pharmacology, molecular docking, and experimental verification","volume":"16","author":"Liu","year":"2025","journal-title":"Front Pharmacol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.molliq.2021.116942","article-title":"Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2","volume":"342","author":"Yadav","year":"2021","journal-title":"J Mol Liq"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158345","article-title":"Vericiguat ameliorates cardiac fibrosis via the sGC-cGMP-PKG pathway in a mouse model of pressure overload","volume":"23","author":"Locatelli","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.112771","article-title":"Nepeta angustifolia C. Y. Wu improves renal injury in HFD\/STZ-induced diabetic nephropathy and inhibits oxidative stress-induced apoptosis of mesangial cells","volume":"255","author":"Huang","year":"2020","journal-title":"J Ethnopharmacol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12964-025-02166-3","article-title":"REST contributes to renal fibrosis through inducing mitochondrial energy metabolism imbalance in tubular epithelial cells","volume":"23","author":"Yang","year":"2025","journal-title":"Cell Commun Signal"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2020.115130","article-title":"Cyclosporine A induces renal tubular epithelial-mesenchymal transition via the PI3K\/Akt signaling pathway","volume":"402","author":"Guo","year":"2020","journal-title":"Toxicol Appl Pharmacol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14458","article-title":"Melatonin attenuates cyclosporine A-induced renal fibrosis by inhibiting the AKT\/mTOR signaling pathway","volume":"23","author":"Salavaty","year":"2019","journal-title":"J Cell Mol Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s12325-021-01927-z","article-title":"A narrative review of chronic kidney disease in clinical practice: current challenges and future perspectives","volume":"39","author":"Evans","year":"2022","journal-title":"Adv Ther"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32064-5","article-title":"Chronic kidney disease","volume":"389","author":"Webster","year":"2017","journal-title":"Lancet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/s41392-022-01036-5","article-title":"Signaling pathways of chronic kidney diseases, implications for therapeutics","volume":"7","author":"Yuan","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B36","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41581-022-00592-x","article-title":"Immunometabolic rewiring of tubular epithelial cells in kidney disease","volume":"18","author":"van der Rijt","year":"2022","journal-title":"Nat Rev Nephrol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"74","DOI":"10.59556\/japi.71.0417","article-title":"Drug-induced kidney disease: revisited","volume":"72","author":"Ganguli","year":"2024","journal-title":"J Assoc Physicians Indi"},{"key":"B38","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.pop.2020.08.006","article-title":"Renal repercussions of medications","volume":"47","author":"Shaddock","year":"2020","journal-title":"Prim Care"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01156-w","article-title":"Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis","volume":"45","author":"Wang","year":"2024","journal-title":"Acta Pharmacol Sin"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e59693","DOI":"10.1371\/journal.pone.0059693","article-title":"Human adipose tissue derived mesenchymal stem cells aggravate chronic cyclosporin nephrotoxicity by the induction of oxidative stress","volume":"8","author":"Chung","year":"2013","journal-title":"PloS One"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2004.45.6.1004","article-title":"Chronic cyclosporine nephrotoxicity: new insights and preventive strategies","volume":"45","author":"Li","year":"2004","journal-title":"Yonsei Med J"},{"key":"B42","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1254\/jphs.fmj05003x4","article-title":"Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis","volume":"100","author":"Tamada","year":"2006","journal-title":"J Pharmacol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.3c11514","article-title":"Nanoceria-mediated cyclosporin A delivery for dry eye disease management through modulating immune-epithelial crosstalk","volume":"18","author":"Cui","year":"2024","journal-title":"ACS Nano"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401830","article-title":"Reactive oxygen species mediate crosstalk between NF-kappaB and JNK","volume":"13","author":"Nakano","year":"2006","journal-title":"Cell Death Differ"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/biom11081144","article-title":"Mitochondrial redox signaling and oxidative stress in kidney diseases","volume":"11","author":"Aranda-Rivera","year":"2021","journal-title":"Biomolecules"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.09.009","article-title":"Reciprocal regulation of TGF-\u03b2 and reactive oxygen species: A perverse cycle for fibrosis","volume":"6","author":"Liu","year":"2015","journal-title":"Redox Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.71595","article-title":"Smad3 signatures in renal inflammation and fibrosis","volume":"18","author":"Wu","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24044004","article-title":"Fibrosis: types, effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation","volume":"24","author":"Antar","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.11.010","article-title":"Inflammation and fibrosis","author":"Mack","year":"2018","journal-title":"Matrix Biol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae258","article-title":"Combination therapy as a new standard of care in diabetic and non-diabetic chronic kidney disease","volume":"40","author":"Neuen","year":"2025","journal-title":"Nephrol Dial Transplant"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1756582\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:39:13Z","timestamp":1769495953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1756582\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2025.1756582"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1756582","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"article-number":"1756582"}}