{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:54:55Z","timestamp":1781376895132,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,11]]},"group-title":"Physiology","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21CA 290420"],"award-info":[{"award-number":["R21CA 290420"]}]},{"name":"NIH","award":["P20GM113226"],"award-info":[{"award-number":["P20GM113226"]}]},{"name":"NIH","award":["R01CA279748"],"award-info":[{"award-number":["R01CA279748"]}]},{"name":"NIH","award":["R01HL168198"],"award-info":[{"award-number":["R01HL168198"]}]},{"name":"NIH","award":["R01HL147844"],"award-info":[{"award-number":["R01HL147844"]}]},{"name":"NIH","award":["U01AA026934"],"award-info":[{"award-number":["U01AA026934"]}]},{"name":"Jewish Heritage Fund for Excellence Pilot Grant Program at the University of Louisville School of Medicine"},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["23TPA1141824"],"award-info":[{"award-number":["23TPA1141824"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Veterans Administration","award":["I01BX002996"],"award-info":[{"award-number":["I01BX002996"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,11]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK\/PKM2\/HIF-2\u03b1 axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-\u03b1; this effect is abrogated by a KHK inhibitor and genetic\n                  <jats:italic>Khk<\/jats:italic>\n                  deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF-\u03b1 stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF-\u03b1 stability in\n                  <jats:italic>Khk<\/jats:italic>\n                  -deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely,\n                  <jats:italic>Khk<\/jats:italic>\n                  -deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover,\n                  <jats:italic>Khk<\/jats:italic>\n                  deficiency inhibits iron absorption in a HIF-2\u03b1-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>In brief<\/jats:title>\n                  <jats:p>Mitchell et al. demonstrate that fructose consumption increases plasma iron levels, while KHK deficiency inhibits iron absorption in a HIF-2\u03b1-dependent manner. Mechanistically, dietary fructose-induced metabolic reprogramming aberrantly stabilizes intestinal HIF-\u03b1, which is mediated by PKM2. Fructose promotes MASH and HCC progression in an iron-dependent manner.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Fructose aberrantly stabilizes intestinal HIF-\u03b1<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>KHK is required for intestinal HIF-\u03b1 stability<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>KHK deficiency inhibits iron absorption in a HIF-2\u03b1-dependent manner<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Dietary fructose promotes MASH and HCC progression in an iron-dependent manner<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.07.729655","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T14:50:31Z","timestamp":1781189431000},"source":"Crossref","is-referenced-by-count":0,"title":["Dietary fructose promotes MASH\/HCC progression through enhanced intestinal HIF-2\u03b1-dependent iron absorption"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8852-839X","authenticated-orcid":false,"given":"Robert A.","family":"Mitchell","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Immunotherapy, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"UofL Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7002-4978","authenticated-orcid":false,"given":"Manman","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5825-9717","authenticated-orcid":false,"given":"Elizabeth","family":"Hudson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Sequencing Technology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-1105","authenticated-orcid":false,"given":"Madison S.","family":"Teer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Environmental Medicine, Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5332-8286","authenticated-orcid":false,"given":"Bradford G.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Environmental Medicine, Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-8939","authenticated-orcid":false,"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Hepatobiology&Toxicology Program, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8459-6953","authenticated-orcid":false,"given":"Ming","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Hepatobiology&Toxicology Program, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061311152502000_2026.06.07.729655v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00627-6"},{"key":"2026061311152502000_2026.06.07.729655v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.12618"},{"key":"2026061311152502000_2026.06.07.729655v1.3","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00019.2009"},{"key":"2026061311152502000_2026.06.07.729655v1.4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94585"},{"key":"2026061311152502000_2026.06.07.729655v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.09.003"},{"key":"2026061311152502000_2026.06.07.729655v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.12.016"},{"key":"2026061311152502000_2026.06.07.729655v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0222-9"},{"key":"2026061311152502000_2026.06.07.729655v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.05.012"},{"key":"2026061311152502000_2026.06.07.729655v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03827-2"},{"key":"2026061311152502000_2026.06.07.729655v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2101-7"},{"key":"2026061311152502000_2026.06.07.729655v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0261-2"},{"key":"2026061311152502000_2026.06.07.729655v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature14508"},{"key":"2026061311152502000_2026.06.07.729655v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab3896"},{"key":"2026061311152502000_2026.06.07.729655v1.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84429"},{"key":"2026061311152502000_2026.06.07.729655v1.15","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00191.2015"},{"key":"2026061311152502000_2026.06.07.729655v1.16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38499"},{"key":"2026061311152502000_2026.06.07.729655v1.17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200524356"},{"key":"2026061311152502000_2026.06.07.729655v1.18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122359"},{"key":"2026061311152502000_2026.06.07.729655v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4412"},{"key":"2026061311152502000_2026.06.07.729655v1.20","doi-asserted-by":"publisher","DOI":"10.1172\/jci144206"},{"key":"2026061311152502000_2026.06.07.729655v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.03.054"},{"key":"2026061311152502000_2026.06.07.729655v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509459103"},{"key":"2026061311152502000_2026.06.07.729655v1.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021013452"},{"key":"2026061311152502000_2026.06.07.729655v1.24","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.12.3226"},{"key":"2026061311152502000_2026.06.07.729655v1.25","doi-asserted-by":"publisher","DOI":"10.1097\/hc9.0000000000000572"},{"key":"2026061311152502000_2026.06.07.729655v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/chemse\/bjv002"},{"key":"2026061311152502000_2026.06.07.729655v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3318"},{"key":"2026061311152502000_2026.06.07.729655v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.03.005"},{"key":"2026061311152502000_2026.06.07.729655v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(70)91066-1"},{"key":"2026061311152502000_2026.06.07.729655v1.30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0026-0495(86)90180-0","article-title":"The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis","volume":"35","year":"1986","journal-title":"Metabolism: clinical and experimental"},{"key":"2026061311152502000_2026.06.07.729655v1.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801791200"},{"key":"2026061311152502000_2026.06.07.729655v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.04.004"},{"key":"2026061311152502000_2026.06.07.729655v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.08.011"},{"key":"2026061311152502000_2026.06.07.729655v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nri3738"},{"key":"2026061311152502000_2026.06.07.729655v1.35","doi-asserted-by":"publisher","DOI":"10.1039\/C6MD00043F"},{"key":"2026061311152502000_2026.06.07.729655v1.36","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00128.2010"},{"key":"2026061311152502000_2026.06.07.729655v1.37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314197110"},{"key":"2026061311152502000_2026.06.07.729655v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.11.020"},{"key":"2026061311152502000_2026.06.07.729655v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.137"},{"key":"2026061311152502000_2026.06.07.729655v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5436"},{"key":"2026061311152502000_2026.06.07.729655v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.01.012"},{"key":"2026061311152502000_2026.06.07.729655v1.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117773108"},{"key":"2026061311152502000_2026.06.07.729655v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.11.022"},{"key":"2026061311152502000_2026.06.07.729655v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nature11986"},{"key":"2026061311152502000_2026.06.07.729655v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/nature17393"},{"key":"2026061311152502000_2026.06.07.729655v1.46","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.052705.162653"},{"key":"2026061311152502000_2026.06.07.729655v1.47","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq4469"},{"key":"2026061311152502000_2026.06.07.729655v1.48","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq5384"},{"key":"2026061311152502000_2026.06.07.729655v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.8"},{"key":"2026061311152502000_2026.06.07.729655v1.50","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-03-562660"},{"key":"2026061311152502000_2026.06.07.729655v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.12.012"},{"key":"2026061311152502000_2026.06.07.729655v1.52","doi-asserted-by":"publisher","DOI":"10.1007\/s00795-013-0016-1"},{"key":"2026061311152502000_2026.06.07.729655v1.53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811029115"},{"key":"2026061311152502000_2026.06.07.729655v1.54","doi-asserted-by":"publisher","DOI":"10.3945\/jn.108.098186"},{"key":"2026061311152502000_2026.06.07.729655v1.55","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37385"},{"key":"2026061311152502000_2026.06.07.729655v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.02.002"},{"key":"2026061311152502000_2026.06.07.729655v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nature10602"},{"key":"2026061311152502000_2026.06.07.729655v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21461-4"},{"key":"2026061311152502000_2026.06.07.729655v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.06.017"},{"key":"2026061311152502000_2026.06.07.729655v1.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261708798"},{"key":"2026061311152502000_2026.06.07.729655v1.61","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202050202"},{"key":"2026061311152502000_2026.06.07.729655v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2013.168"},{"key":"2026061311152502000_2026.06.07.729655v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.05.004"},{"key":"2026061311152502000_2026.06.07.729655v1.64","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.011188"},{"key":"2026061311152502000_2026.06.07.729655v1.65","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12993"},{"key":"2026061311152502000_2026.06.07.729655v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2023.102315"},{"key":"2026061311152502000_2026.06.07.729655v1.67","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2016.1177677"},{"key":"2026061311152502000_2026.06.07.729655v1.68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119908109"},{"key":"2026061311152502000_2026.06.07.729655v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3338"},{"key":"2026061311152502000_2026.06.07.729655v1.70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19263-1"},{"key":"2026061311152502000_2026.06.07.729655v1.71","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00015-07"},{"key":"2026061311152502000_2026.06.07.729655v1.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-66064-5"},{"key":"2026061311152502000_2026.06.07.729655v1.73","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20042"},{"key":"2026061311152502000_2026.06.07.729655v1.74","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1220-4"},{"key":"2026061311152502000_2026.06.07.729655v1.75","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101196"},{"key":"2026061311152502000_2026.06.07.729655v1.76","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29914"},{"key":"2026061311152502000_2026.06.07.729655v1.77","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.12.052"},{"key":"2026061311152502000_2026.06.07.729655v1.78","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im0320s110"},{"key":"2026061311152502000_2026.06.07.729655v1.79","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.109400"},{"key":"2026061311152502000_2026.06.07.729655v1.80","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100386"},{"key":"2026061311152502000_2026.06.07.729655v1.81","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.002"},{"key":"2026061311152502000_2026.06.07.729655v1.82","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.07.729655","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:15:36Z","timestamp":1781374536000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.07.729655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":82,"URL":"https:\/\/doi.org\/10.64898\/2026.06.07.729655","relation":{},"subject":[],"published":{"date-parts":[[2026,6,11]]},"subtype":"preprint"}}