{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:14Z","timestamp":1789970534743,"version":"4.0.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Atrial fibrillation (AF) develops through the interplay of electrical, structural, inflammatory, and metabolic remodeling. However, the circadian-associated molecular characteristics of the diseased human atrium remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated differential expression analysis, circadian gene intersection, weighted gene co-expression network analysis, and complementary feature selection algorithms in a discovery cohort. The prioritized candidate genes were subsequently validated using an independent atrial dataset, human atrial rhythmicity data, single-nucleus transcriptomics, and experimental evidence derived from human and mouse atrial tissues. We additionally performed cross-cohort drug repurposing screening and exploratory molecular docking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ANGPTL2 and CP were identified as prioritized candidate genes associated with circadian rhythms. Both genes were consistently upregulated in fibrillating atria but exhibited distinct expression profiles: ANGPTL2 demonstrated stronger discriminatory power at the tissue level, whereas CP showed a larger but more heterogeneous expression alteration. Both genes displayed rhythmic expression patterns in human atrial appendage tissue and were predominantly enriched in vascular and stromal cell populations, establishing a link between temporal atrial biology and inflammatory-metabolic remodeling as well as copper-redox remodeling. The upregulation of their transcripts and proteins was further validated across independent human samples and an arrhythmia-prone mouse model. No compound met the prespecified multi-source criteria for cross-cohort drug repurposing. An independent exploratory analysis of clinically used antiarrhythmic drugs identified favorable molecular docking profiles for both target proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>ANGPTL2 and CP are externally validated circadian rhythm-associated candidate genes for atrial fibrillation (AF), and may yield experimentally testable candidate gene-drug pairs. However, these findings do not establish causal regulation by the circadian clock, direct molecular binding, or clinical therapeutic efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1949794","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:36:38Z","timestamp":1789968998000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ANGPTL2 and CP define complementary circadian-associated signals in atrial fibrillation: integrative transcriptomics and external validation"],"prefix":"10.3389","volume":"14","author":[{"given":"Jiahui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyu","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Affiliated Hospital of Putian University","place":["Putian, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1016\/j.jacc.2022.03.379","article-title":"Inflammasome signaling in atrial fibrillation","volume":"79","author":"Ajoolabady","year":"2022","journal-title":"J. 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