{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:46:57Z","timestamp":1791809217240,"version":"4.3.4"},"reference-count":45,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81470992"],"award-info":[{"award-number":["No. 81470992"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Patients receiving continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) frequently experience systemic citrate accumulation, yet its immunometabolic consequences remain poorly understood. Here, we examined how supraphysiological citrate shapes macrophage inflammatory responses using isotope tracing, targeted metabolomics, and in\u00a0vitro and in\u00a0vivo inflammatory models. In LPS\u2010stimulated THP\u20101 cells, U\u2010\n                    <jats:sup>13<\/jats:sup>\n                    C\u2010citrate was preferentially retained in proximal citrate\u2010associated metabolite pools, with robust labeling of citrate,\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010aconitate, and itaconate, but minimal labeling of downstream tricarboxylic acid (TCA)\u2010related or glycolytic intermediates. Citrate exposure also increased proximal citrate\u2010related metabolite pools, while acetyl\u2010CoA levels were more strongly increased at 1\u2009mM than at 6\u2009mM. U\u2010\n                    <jats:sup>13<\/jats:sup>\n                    C\u2010glucose tracing further showed that citrate exposure redistributed glucose\u2010derived carbon, increasing its retention in glycolysis\u2010 and pentose phosphate pathway\u2010related intermediates while reducing its relative contribution to proximal TCA\u2010related metabolites. Consistent with this, citrate increased extracellular acidification rate and upregulated GLUT1 and PKM2. In THP\u20101 cells, PBMCs, and BMDMs, citrate amplified LPS\u2010induced cytokine production in a nonmonotonic manner, with 1\u2009mM generally producing a stronger proinflammatory effect than 6\u2009mM. In\u00a0vivo, citrate administration exacerbated hypercytokinemia and increased M1 macrophage polarization in LPS\u2010treated mice. Moreover, citrate\u2010induced proinflammatory responses were attenuated by inhibition of glycolysis, citrate\u2010to\u2010acetyl\u2010CoA conversion, or histone acetylation. Collectively, supraphysiological citrate promotes monocyte\/macrophage proinflammatory activation through metabolic and epigenetic reprogramming, with a nonlinear dose response. These findings suggest that systemic citrate accumulation during CRRT may aggravate inflammatory tissue or organ injury and should be considered carefully in inflammatory settings.\n                  <\/jats:p>","DOI":"10.1096\/fj.202601873rr","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:16:48Z","timestamp":1791465408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Supraphysiological Citrate Exposure Drives Nonmonotonic Immunometabolic Reprogramming and Proinflammatory Activation in Monocytes\/Macrophages"],"prefix":"10.1096","volume":"40","author":[{"given":"Xiaoyan","family":"Gu","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Kidney Diseases, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Lu","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Kidney Diseases, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine Nanjing First Hospital, Nanjing Medical University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Nan","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Kidney Diseases, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxia","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Kidney Diseases, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8434-8172","authenticated-orcid":false,"given":"Dehua","family":"Gong","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Kidney Diseases, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University  Nanjing Jiangsu Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1398384"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/kisup.2011.35"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-017-1880-1"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40560-015-0102-7"},{"key":"e_1_2_11_6_1","article-title":"Plasma Citrate Homeostasis: How It Is Regulated; and Its Physiological and Clinical Implications. An Important, but Neglected, Relationship in Medicine","volume":"1","author":"Costello L. C.","year":"2016","journal-title":"HSOA Journal of Human Endocrinology"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0182134"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-023-00457-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s44158-023-00091-w"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfac223"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000513150"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2006.07.016"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000084871.76568.E6"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-002-0963-6"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.18618"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-47644-1"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-03-419747"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-249540"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11986"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13110916"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1733"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.123.3191.309"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03442-1"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59643"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.03.008"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13668-3"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2026.01.028"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.09.037"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3838"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12062"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42916-1"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.06.004"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-025-07948-4"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1199751"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.02.005"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)40658-3"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.009"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MIR1118-415R"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5533793"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.5301\/ijao.5000558"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2369-15-19"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-016-1299-0"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00071"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052900"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1159\/000529350"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601873RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202601873RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601873RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:08:46Z","timestamp":1791806926000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202601873RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":45,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,10,15]]}},"alternative-id":["10.1096\/fj.202601873RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202601873rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72326"}}