{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:32Z","timestamp":1788415952947,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"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. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant associated with cardiovascular dysfunction, but the molecular links between PFOA exposure and atrial fibrillation (AF) remain unclear. We aimed to prioritize a candidate mediator connecting PFOA with AF and examine its associated molecular effects in atrial cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PFOA-associated or computationally predicted genes from CTD, STITCH, and SwissTargetPrediction were integrated with AF-associated genes. Complement factor B (CFB) was evaluated using exploratory Mendelian randomization, public single-cell analysis, protein-interaction and enrichment analyses, molecular docking, a single 100-ns molecular dynamics trajectory, and HL-1 cell experiments. Cells were exposed to 25\u2005\u03bcM PFOA for 48\u2005h with or without CFB silencing, followed by qRT-PCR, Western blotting, immunofluorescence, and CCK-8 assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CFB was the only shared candidate between the integrated PFOA-related target set and the filtered AF-associated gene set. Genetically predicted plasma CFB levels were positively associated with AF risk (odds ratio\u2009=\u20091.109, 95% confidence interval: 1.021\u20131.205; FDR-adjusted\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.015). Public single-cell data showed preferential basal CFB expression in cardiac fibroblast and stromal populations, with lower expression in cardiomyocytes. The predicted PFOA\u2013CFB pose remained within the selected pocket during the sampled trajectory. In HL-1 cells, PFOA increased CFB mRNA and protein abundance, decreased CACNA1C transcript levels without significantly changing CACNA1C protein abundance, and increased KCNJ2 and NPPA expression. CFB silencing attenuated the PFOA-associated increases in KCNJ2 and NPPA, whereas CACNA1C showed no corresponding rescue pattern. CFB immunoreactivity was detected within cTnT-positive, PFOA-exposed HL-1 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings prioritize CFB as a candidate molecule potentially associated with PFOA exposure and AF-related molecular alterations. They do not establish direct PFOA\u2013CFB binding, functional complement activation, causality, electrical remodeling, or a functional AF phenotype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1759840","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:14:46Z","timestamp":1788412486000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Perfluorooctanoic acid\u2013associated complement factor B upregulation and atrial fibrillation\u2013related molecular alterations: integrated network toxicology, Mendelian randomization, molecular dynamics, and HL-1 cell analyses"],"prefix":"10.3389","volume":"13","author":[{"given":"Dan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University","place":["Wuhan, Hubei, China"]},{"name":"Department of Cardiovascular Surgery, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery","place":["Wuhan, Hubei, China"]},{"name":"Department of Cardiovascular Surgery, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease","place":["Wuhan, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanfeng","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University","place":["Wuhan, Hubei, China"]},{"name":"Department of Cardiovascular Surgery, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery","place":["Wuhan, Hubei, 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