{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T18:30:34Z","timestamp":1785868234976,"version":"3.56.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fujian provincial key Clinical Specialty Construction Project","award":["2017ZDZKMN"],"award-info":[{"award-number":["2017ZDZKMN"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Patients with kidney stones (KS) often have an increased risk of atherosclerosis (AS). Because endothelial dysfunction (ED) is closely associated with AS, its role in KS remains unclear. This study aimed to examine the roles and mechanisms of AS-related ED genes in KS. Three datasets (GSE73680, GSE117518, and GSE132651) were analyzed. Differential expression analysis was conducted to identify differentially expressed genes (DEGs). To identify potential biomarkers, least absolute shrinkage and selection operator (LASSO) regression analysis and expression validation were conducted. Further analyses including GeneMANIA, gene set enrichment analysis (GSEA), examination of biomarkers within immune cells and subcellular localization analysis, molecular regulatory network analysis, tissue specificity analysis, and competing endogenous (ceRNA) network analysis were employed to comprehensively explore the functions and regulatory mechanisms of the identified biomarkers. Moreover, drug prediction analysis was conducted. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was proceeded to verify the expression levels of the biomarkers. A total of 22 DEGs associated with KS and AS were identified. Lasso regression selected 4 candidate biomarkers (MMP10, UCHL1, NEK2, and HEY1), among which UCHL1 and NEK2 were validated as key biomarkers. GeneMANIA and GSEA analyses uncovered the potential involvement of these biomarkers in cell adhesion molecules, focal adhesion, and lysosome pathways. Analysis of immune cells and subcellular localization provided insight into the biological functions and intracellular distribution of the biomarkers. Transcription factor regulatory network and ceRNA network analyses elucidated potential upstream regulatory mechanisms. Drug prediction analysis identified 17 potential drugs, including pazopanib and palbociclib, that may target NEK2. RT-qPCR demonstrated that\n                    <jats:italic>NEK2<\/jats:italic>\n                    was significantly overexpressed in KS samples. This study identified biomarkers associated with KS and AS and comprehensively analyzed their molecular regulatory networks. These findings provide novel understandings of the molecular mechanism underlying KS and lay the foundation for future personalized treatment and drug development.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0354595","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:32:48Z","timestamp":1785864768000},"page":"e0354595","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bioinformatics and experimental studies of atherosclerosis-related endothelial dysfunction genes in renal calculi and exploration of their molecular mechanisms"],"prefix":"10.1371","volume":"21","author":[{"given":"Aina","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenjing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangshen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3843-9472","authenticated-orcid":true,"given":"Changyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"5","key":"pone.0354595.ref001","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.3390\/ijms25053075","article-title":"Pathophysiology and Main Molecular Mechanisms of Urinary Stone Formation and Recurrence","volume":"25","author":"F Tamborino","year":"2024","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0354595.ref002","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.eururo.2012.06.009","article-title":"Re: Charles D. Scales Jr., Alexandria C. Smith, Janet M. Hanley, Christopher S. Saigal, Urologic Diseases in America Project. Prevalence of kidney stones in the United States","volume":"62","author":"SN Thornton","year":"2012","journal-title":"Eur Urol"},{"key":"pone.0354595.ref003","doi-asserted-by":"crossref","first-page":"41630","DOI":"10.1038\/srep41630","article-title":"Prevalence of kidney stones in mainland China: A systematic review","volume":"7","author":"W Wang","year":"2017","journal-title":"Sci Rep"},{"issue":"11","key":"pone.0354595.ref004","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/s41581-025-00990-x","article-title":"Kidney stone disease: risk factors, pathophysiology and management","volume":"21","author":"M Bargagli","year":"2025","journal-title":"Nat Rev Nephrol"},{"issue":"3","key":"pone.0354595.ref005","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.eururo.2015.07.040","article-title":"EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis","volume":"69","author":"C T\u00fcrk","year":"2016","journal-title":"European urology"},{"key":"pone.0354595.ref006","first-page":"3068365","article-title":"Kidney Stone Disease: An Update on Current Concepts","author":"T Alelign","year":"2018","journal-title":"Adv Urol"},{"issue":"4","key":"pone.0354595.ref007","doi-asserted-by":"crossref","first-page":"804","DOI":"10.2215\/CJN.05811108","article-title":"Kidney stones and the risk for chronic kidney disease","volume":"4","author":"AD Rule","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"issue":"6","key":"pone.0354595.ref008","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1042\/CS20171574","article-title":"Cross-talk between renal lithogenesis and atherosclerosis: an unveiled link between kidney stone formation and cardiovascular diseases","volume":"132","author":"A Devarajan","year":"2018","journal-title":"Clin Sci (Lond)"},{"issue":"8","key":"pone.0354595.ref009","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1007\/s11255-021-03058-4","article-title":"Association between aortic calcification and the presence of kidney stones: calcium oxalate calculi in focus","volume":"54","author":"B Li","year":"2022","journal-title":"Int Urol Nephrol"},{"issue":"3","key":"pone.0354595.ref010","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.numecd.2023.09.011","article-title":"Epidemiological and biological associations between cardiovascular disease and kidney stone formation: A systematic review and meta-analysis","volume":"34","author":"L Muschialli","year":"2024","journal-title":"Nutr Metab Cardiovasc Dis"},{"issue":"4","key":"pone.0354595.ref011","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"MA Gimbrone","year":"2016","journal-title":"Circ Res"},{"issue":"23","key":"pone.0354595.ref012","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.jacc.2009.09.009","article-title":"Inflammation in atherosclerosis: from pathophysiology to practice","volume":"54","author":"P Libby","year":"2009","journal-title":"J Am Coll Cardiol"},{"issue":"8","key":"pone.0354595.ref013","article-title":"Endothelial dysfunction: molecular mechanisms and clinical implications","volume":"5","author":"X Wang","year":"2024","journal-title":"MedComm (2020)"},{"issue":"3","key":"pone.0354595.ref014","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1053\/j.ajkd.2014.03.017","article-title":"Kidney stones and cardiovascular risk: a meta-analysis of cohort studies","volume":"64","author":"Y Liu","year":"2014","journal-title":"Am J Kidney Dis"},{"issue":"2","key":"pone.0354595.ref015","doi-asserted-by":"crossref","first-page":"912","DOI":"10.3390\/ijms23020912","article-title":"Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases","volume":"23","author":"J Saenz-Medina","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0354595.ref016","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1681\/ASN.2015111271","article-title":"Genome-Wide Gene Expression Profiling of Randall\u2019s Plaques in Calcium Oxalate Stone Formers","volume":"28","author":"K Taguchi","year":"2017","journal-title":"J Am Soc Nephrol"},{"issue":"14","key":"pone.0354595.ref017","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.120.016134","article-title":"Abnormal Endothelial Gene Expression Associated With Early Coronary Atherosclerosis","volume":"9","author":"RP Hebbel","year":"2020","journal-title":"J Am Heart Assoc"},{"issue":"7","key":"pone.0354595.ref018","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"15","key":"pone.0354595.ref019","doi-asserted-by":"crossref","first-page":"3844","DOI":"10.1093\/bioinformatics\/btac409","article-title":"ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2","volume":"38","author":"EK Gustavsson","year":"2022","journal-title":"Bioinformatics"},{"issue":"18","key":"pone.0354595.ref020","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Z Gu","year":"2016","journal-title":"Bioinformatics"},{"issue":"21","key":"pone.0354595.ref021","doi-asserted-by":"crossref","first-page":"6605","DOI":"10.1111\/febs.16095","article-title":"Venn diagram analysis overestimates the extent of circadian rhythm reprogramming","volume":"289","author":"A Pelikan","year":"2022","journal-title":"FEBS J"},{"issue":"1","key":"pone.0354595.ref022","doi-asserted-by":"crossref","first-page":"11340","DOI":"10.1038\/s41598-022-15609-5","article-title":"Applying logistic LASSO regression for the diagnosis of atypical Crohn\u2019s disease","volume":"12","author":"Y Li","year":"2022","journal-title":"Sci Rep"},{"key":"pone.0354595.ref023","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"S H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"issue":"11","key":"pone.0354595.ref024","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Res"},{"key":"pone.0354595.ref025","article-title":"Kidney stones: a global picture of prevalence, incidence, and associated risk factors","volume":"12","author":"V Romero","year":"2010","journal-title":"Rev Urol"},{"key":"pone.0354595.ref026","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.juro.2015.10.001","article-title":"Coronary Artery Calcium Score and Association with Recurrent Nephrolithiasis: The Multi-Ethnic Study of Atherosclerosis","volume":"195","author":"RS Hsi","year":"2016","journal-title":"J Urol"},{"issue":"3","key":"pone.0354595.ref027","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.juro.2010.10.086","article-title":"Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study","volume":"185","author":"AP Reiner","year":"2011","journal-title":"J Urol"},{"issue":"12","key":"pone.0354595.ref028","article-title":"Age- and oxidative stress-induced centrosome amplification and renal stones in Drosophila Malpighian tubules","volume":"13","author":"H-J Na","year":"2024","journal-title":"Biol Open"},{"issue":"9","key":"pone.0354595.ref029","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.3390\/ijms17091404","article-title":"Wnt\/\u03b2-Catenin Signaling Mediated-UCH-L1 Expression in Podocytes of Diabetic Nephropathy","volume":"17","author":"H Zhang","year":"2016","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0354595.ref030","doi-asserted-by":"crossref","DOI":"10.1152\/ajplung.00492.2020","article-title":"UCHL1, a deubiquitinating enzyme, regulates lung endothelial cell permeability in vitro and in vivo","volume":"320","author":"S Mitra","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"1","key":"pone.0354595.ref031","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00018-024-05186-3","article-title":"Deubiquitinase UCHL1 promotes angiogenesis and blood-spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17","volume":"81","author":"J Wang","year":"2024","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"pone.0354595.ref032","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1161\/CIRCULATIONAHA.123.065304","article-title":"Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension","volume":"150","author":"H Tang","year":"2024","journal-title":"Circulation"},{"issue":"1","key":"pone.0354595.ref033","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.kint.2017.05.016","article-title":"Ubiquitin C-Terminal Hydrolase L1 is required for regulated protein degradation through the ubiquitin proteasome system in kidney","volume":"93","author":"V Rad\u00f3n","year":"2018","journal-title":"Kidney Int"},{"issue":"1","key":"pone.0354595.ref034","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.molmed.2024.07.013","article-title":"Role of NEK2 in tumorigenesis and tumor progression","volume":"31","author":"J Xia","year":"2025","journal-title":"Trends Mol Med"},{"key":"pone.0354595.ref035","doi-asserted-by":"crossref","first-page":"104651","DOI":"10.1016\/j.mvr.2023.104651","article-title":"Involvement of NEK2 and NEK9 in LPS - induced endothelial barrier dysfunction","volume":"152","author":"N Barabutis","year":"2024","journal-title":"Microvasc Res"},{"key":"pone.0354595.ref036","doi-asserted-by":"crossref","first-page":"100002","DOI":"10.1016\/j.aspetd.2025.100002","article-title":"NEK2 inhibition alleviates lipopolysaccharide-induced endothelial injury","volume":"1","author":"S Fakir","year":"2025","journal-title":"ASPET Discov"},{"issue":"6","key":"pone.0354595.ref037","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41581-020-00392-1","article-title":"Randall\u2019s plaque and calcium oxalate stone formation: role for immunity and inflammation","volume":"17","author":"SR Khan","year":"2021","journal-title":"Nat Rev Nephrol"},{"key":"pone.0354595.ref038","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3389\/fonc.2015.00278","article-title":"Aurora Kinase Inhibitors: Current Status and Outlook","volume":"5","author":"V Bavetsias","year":"2015","journal-title":"Frontiers in oncology"},{"key":"pone.0354595.ref039","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.bbapap.2003.11.016","article-title":"Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential","volume":"1697","author":"MA Bogoyevitch","year":"2004","journal-title":"Biochim Biophys Acta"},{"issue":"20","key":"pone.0354595.ref040","doi-asserted-by":"crossref","first-page":"10962","DOI":"10.3390\/ijms222010962","article-title":"FosL1 Is a Novel Target of Levetiracetam for Suppressing the Microglial Inflammatory Reaction","volume":"22","author":"K Niidome","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"10","key":"pone.0354595.ref041","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1016\/j.ymthe.2022.05.019","article-title":"Neat1 promotes acute kidney injury to chronic kidney disease by facilitating tubular epithelial cells apoptosis via sequestering miR-129-5p","volume":"30","author":"T Ma","year":"2022","journal-title":"Mol Ther"},{"issue":"6","key":"pone.0354595.ref042","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1161\/ATVBAHA.123.319251","article-title":"Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications","volume":"43","author":"Q Yang","year":"2023","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"pone.0354595.ref043","doi-asserted-by":"crossref","first-page":"227","DOI":"10.20892\/j.issn.2095-3941.2020.0186","article-title":"Nobiletin downregulates the SKP2-p21\/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma","volume":"18","author":"T Chen","year":"2021","journal-title":"Cancer Biol Med"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0354595","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:32:56Z","timestamp":1785864776000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0354595"}},"subtitle":[],"editor":[{"given":"Patrick","family":"Goymer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0354595","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}