{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T20:11:57Z","timestamp":1793218317908,"version":"4.5.0"},"reference-count":158,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Pharmacological Research"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.phrs.2026.108330","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T20:29:42Z","timestamp":1782851382000},"page":"108330","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"special_numbering":"C","title":["Ketohexokinase: A central mediator of fructose-associated pathogenesis and promising therapeutic target"],"prefix":"10.1016","volume":"230","author":[{"given":"Haihong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1113\/jphysiol.2011.215731","article-title":"The role of fructose transporters in diseases linked to excessive fructose intake","volume":"591","author":"Douard","year":"2013","journal-title":"J. Physiol."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1152\/physrev.00019.2009","article-title":"Metabolic effects of fructose and the worldwide increase in obesity","volume":"90","author":"Tappy","year":"2010","journal-title":"Physiol. Rev."},{"issue":"12","key":"10.1016\/j.phrs.2026.108330_bib3","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1016\/j.cmet.2021.09.004","article-title":"\"Sweet death\": fructose as a metabolic toxin that targets the gut-liver axis","volume":"33","author":"Febbraio","year":"2021","journal-title":"Cell. Metab."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib4","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.nut.2013.08.014","article-title":"Association of fructose consumption and components of metabolic syndrome in human studies: a systematic review and meta-analysis","volume":"30","author":"Kelishadi","year":"2014","journal-title":"Nutrition"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib5","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1039\/D1FO03381F","article-title":"Pathophysiological mechanisms of hypertension development induced by fructose consumption","volume":"13","author":"Xu","year":"2022","journal-title":"Food Funct."},{"key":"10.1016\/j.phrs.2026.108330_bib6","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1038\/ncomms3434","article-title":"Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome","volume":"4","author":"Lanaspa","year":"2013","journal-title":"Nat. Commun."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib7","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1172\/JCI94585","article-title":"Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling","volume":"127","author":"Softic","year":"2017","journal-title":"J. Clin. Invest."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib8","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1172\/JCI37385","article-title":"Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight\/obese humans","volume":"119","author":"Stanhope","year":"2009","journal-title":"J. Clin. Invest."},{"issue":"12","key":"10.1016\/j.phrs.2026.108330_bib9","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/j.cmet.2021.09.010","article-title":"Molecular aspects of fructose metabolism and metabolic disease","volume":"33","author":"Herman","year":"2021","journal-title":"Cell. Metab."},{"issue":"910","key":"10.1016\/j.phrs.2026.108330_bib10","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.adt3549","article-title":"Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria","volume":"18","author":"Jackstadt","year":"2025","journal-title":"Sci. Signal."},{"issue":"20","key":"10.1016\/j.phrs.2026.108330_bib11","doi-asserted-by":"crossref","first-page":"4376","DOI":"10.3390\/nu15204376","article-title":"Endogenous fructose production and metabolism drive metabolic dysregulation and liver disease in mice with hereditary fructose intolerance","volume":"15","author":"Andres-Hernando","year":"2023","journal-title":"Nutrients"},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib12","doi-asserted-by":"crossref","first-page":"E685","DOI":"10.1152\/ajpendo.00283.2010","article-title":"Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome","volume":"299","author":"Dekker","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s11892-020-01342-8","article-title":"Tissue-specific fructose metabolism in obesity and diabetes","volume":"20","author":"Helsley","year":"2020","journal-title":"Curr. Diab Rep."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib14","article-title":"Fructose metabolism and disease mechanisms: from nutritional excess to obesity and multiorgan pathophysiology","volume":"18","author":"Sukumaran","year":"2026","journal-title":"Front. Biosci. (Elite Ed."},{"key":"10.1016\/j.phrs.2026.108330_bib15","unstructured":"Steinmann B., Gitzelman R., Van den Berghe G. Disorders of fructose metabolism (8th ed.). In: The Metabolic and Molecular Bases of Inherited Disease, edited by Scriver CR, Beaudet AL, Sly WS. New York: McGraw Hill, 2001, 1489\u20131520."},{"key":"10.1016\/j.phrs.2026.108330_bib16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev.nu.14.070194.000353","article-title":"Inborn errors of fructose metabolism","volume":"14","author":"Van den Berghe","year":"1994","journal-title":"Annu. Rev. Nutr."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib17","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.medj.2021.04.007","article-title":"Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: a randomized phase 2 trial","volume":"2","author":"Kazierad","year":"2021","journal-title":"Med"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib18","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1111\/dom.14946","article-title":"A phase 2a, randomized, double-blind, placebo-controlled, three-arm, parallel-group study to assess the efficacy, safety, tolerability and pharmacodynamics of PF-06835919 in patients with non-alcoholic fatty liver disease and type 2 diabetes","volume":"25","author":"Saxena","year":"2023","journal-title":"Diabetes Obes. Metab."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib19","doi-asserted-by":"crossref","DOI":"10.1172\/JCI187376","article-title":"Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance","volume":"135","author":"Koene","year":"2025","journal-title":"J. Clin. Invest."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib20","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1007\/s13300-025-01752-5","article-title":"LY3522348, A new ketohexokinase inhibitor: a first-in-human study in healthy adults","volume":"16","author":"Fukuda","year":"2025","journal-title":"Diabetes Ther."},{"key":"10.1016\/j.phrs.2026.108330_bib21","unstructured":"Gaughan S., Ayres L., Baker P.R. II. Hereditary Fructose Intolerance. In: Adam M.P., Bick S., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A., editors. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132026, 2015 Dec 17 [updated 2021 Feb 18],"},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib22","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1016\/j.clnu.2021.01.026","article-title":"Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance","volume":"40","author":"Debray","year":"2021","journal-title":"Clin. Nutr."},{"key":"10.1016\/j.phrs.2026.108330_bib23","unstructured":"Bijarnia-Mahay S., Bhatia S., Arora V. Fructose-1,6-Bisphosphatase Deficiency. In: Adam M.P., Bick S., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A., editors. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132026, 2019,"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib24","doi-asserted-by":"crossref","DOI":"10.1111\/apha.70187","article-title":"Pax8-rtTA\/LC1-driven inducible ketohexokinase deletion protects against high fructose-induced metabolic syndrome in mice","volume":"242","author":"Yi","year":"2026","journal-title":"Acta Physiol. (Oxf. )"},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib25","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1369\/jhc.2009.953190","article-title":"Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme","volume":"57","author":"Diggle","year":"2009","journal-title":"J. Histochem. Cytochem."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib26","doi-asserted-by":"crossref","first-page":"E386","DOI":"10.1152\/ajpendo.00027.2018","article-title":"Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects","volume":"315","author":"Miller","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib27","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1042\/bj0870576","article-title":"The post-natal development of hepatic fructokinase","volume":"87","author":"WALKER","year":"1963","journal-title":"Biochem. J."},{"key":"10.1016\/j.phrs.2026.108330_bib28","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/197696a0","article-title":"Essential -SH groups in liver ketohexokinase","volume":"197","author":"Ponz","year":"1963","journal-title":"Nature"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/bj0900261","article-title":"Ketohexokinase, isoenzymes of glucokinase and glycogen synthesis from hexoses in neonatal rat liver","volume":"90","author":"Ballard","year":"1964","journal-title":"Biochem. J."},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib30","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1172\/JCI105872","article-title":"Enzymes of fructose metabolism in human liver","volume":"47","author":"Heinz","year":"1968","journal-title":"J. Clin. Invest."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib31","first-page":"85","article-title":"Enzymes of fructose metabolism in human kidney","volume":"19","author":"Heinz","year":"1975","journal-title":"Enzyme"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib32","first-page":"93","article-title":"Enzymes of fructose metabolism in human small intestine mucosa","volume":"19","author":"Heinz","year":"1975","journal-title":"Enzyme"},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1159\/000265196","article-title":"Investigations of the enzymes involved in the fructose breakdown in the cattle lens","volume":"14","author":"Ohrloff","year":"1982","journal-title":"Ophthalmic Res."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib34","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000265214","article-title":"Presence of ketohexokinase (EC 2.7.1.3) in human lenses","volume":"14","author":"Ohrloff","year":"1982","journal-title":"Ophthalmic Res."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib35","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0014-5793(89)81085-3","article-title":"Presence of fructokinase in pancreatic islets","volume":"255","author":"Malaisse","year":"1989","journal-title":"FEBS Lett."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib36","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.molbrainres.2005.09.019","article-title":"Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum","volume":"142","author":"Funari","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib37","first-page":"517","article-title":"Fructokinase activity in rat liver, ileum, parotid gland, pancreas, pancreatic islet, B and non-B islet cell homogenates","volume":"17","author":"Giroix","year":"2006","journal-title":"Int. J. Mol. Med."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.rvsc.2008.11.004","article-title":"Tissue expression of ketohexokinase in cats","volume":"87","author":"Springer","year":"2009","journal-title":"Res. Vet. Sci."},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib39","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1093\/hmg\/3.9.1627","article-title":"Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase)","volume":"3","author":"Bonthron","year":"1994","journal-title":"Hum. Mol. Genet."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib40","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1007\/s003359900132","article-title":"Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23","volume":"7","author":"Hayward","year":"1996","journal-title":"Mamm. Genome"},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib41","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/s003359900544","article-title":"The genes encoding glucokinase regulatory protein and ketohexokinase co-localize to mouse chromosome 5","volume":"8","author":"Wightman","year":"1997","journal-title":"Mamm. Genome"},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib42","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1046\/j.1432-1327.1998.2570085.x","article-title":"Structure and alternative splicing of the ketohexokinase gene","volume":"257","author":"Hayward","year":"1998","journal-title":"Eur. J. Biochem."},{"issue":"Pt 3","key":"10.1016\/j.phrs.2026.108330_bib43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1107\/S0907444908041115","article-title":"Structures of alternatively spliced isoforms of human ketohexokinase","volume":"65","author":"Trinh","year":"2009","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1152\/physiolgenomics.00128.2010","article-title":"Both isoforms of ketohexokinase are dispensable for normal growth and development","volume":"42A","author":"Diggle","year":"2010","journal-title":"Physiol. Genom."},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib45","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.2337\/diabetes.52.9.2426","article-title":"Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria","volume":"52","author":"Asipu","year":"2003","journal-title":"Diabetes"},{"key":"10.1016\/j.phrs.2026.108330_bib46","doi-asserted-by":"crossref","first-page":"945","DOI":"10.3389\/fgene.2019.00945","article-title":"Heterogeneity in Metabolic Responses to Dietary Fructose","volume":"10","author":"Hou","year":"2019","journal-title":"Front. Genet."},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib47","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2024.107538","article-title":"Residues in the fructose-binding pocket are required for ketohexokinase-A activity","volume":"300","author":"Ferreira","year":"2024","journal-title":"J. Biol. Chem."},{"issue":"Pt 6","key":"10.1016\/j.phrs.2026.108330_bib48","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1107\/S2059798324003723","article-title":"Michaelis-like complex of mouse ketohexokinase isoform C","volume":"80","author":"Gasper","year":"2024","journal-title":"Acta Crystallogr. D. Struct. Biol."},{"issue":"Pt 11","key":"10.1016\/j.phrs.2026.108330_bib49","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1107\/S2053230X25008428","article-title":"Conformational changes in ketohexokinase are conserved across isozymes and species","volume":"81","author":"Bae","year":"2025","journal-title":"Acta Crystallogr. F. Struct. Biol. Commun."},{"key":"10.1016\/j.phrs.2026.108330_bib50","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0076-6879(75)41015-1","article-title":"Estimation of fructokinase (ketohexokinase) in crude tissue preparations","volume":"41","author":"Weiser","year":"1975","journal-title":"Methods Enzymol."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib51","doi-asserted-by":"crossref","DOI":"10.1016\/j.xpro.2021.100731","article-title":"A luminescence-based protocol for assessing fructose metabolism via quantification of ketohexokinase enzymatic activity in mouse or human hepatocytes","volume":"2","author":"Park","year":"2021","journal-title":"STAR Protoc."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib52","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF01856758","article-title":"Adaptative changes of activity of enzymes involved in fructose metabolism in the liver and jejunal mucosa of rats following fructose feeding","volume":"178","author":"Bode","year":"1980","journal-title":"Res. Exp. Med. (Berl. )"},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib53","first-page":"1597","article-title":"The effect of liver-specific ketohexokinase deletion on the intestinal-liver-kidney axis in high-fructose-induced metabolic syndrome mice","volume":"58","author":"Yang","year":"2026","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib54","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1161\/HYPERTENSIONAHA.116.08240","article-title":"Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity","volume":"69","author":"Xu","year":"2017","journal-title":"Hypertension"},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib55","doi-asserted-by":"crossref","first-page":"697","DOI":"10.5650\/jos.ess20340","article-title":"Effects of Dietary Supplementation with Myo-inositol on Hepatic Expression of Glycolytic and Fructolytic Enzyme Genes in Rats Fed a High-sucrose Diet","volume":"70","author":"Hibi","year":"2021","journal-title":"J. Oleo Sci."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib56","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jhep.2023.02.010","article-title":"Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation","volume":"79","author":"Helsley","year":"2023","journal-title":"J. Hepatol."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib57","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.3390\/nu15071778","article-title":"Recent Progress on Fructose Metabolism-Chrebp, Fructolysis, and Polyol Pathway","volume":"15","author":"Iizuka","year":"2023","journal-title":"Nutrients"},{"issue":"10","key":"10.1016\/j.phrs.2026.108330_bib58","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0047948","article-title":"Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver","volume":"7","author":"Lanaspa","year":"2012","journal-title":"PLoS. One"},{"issue":"19","key":"10.1016\/j.phrs.2026.108330_bib59","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1073\/pnas.0401516101","article-title":"Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis","volume":"101","author":"Iizuka","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib60","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3390\/nu10030340","article-title":"ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption","volume":"10","author":"Kato","year":"2018","journal-title":"Nutrients"},{"issue":"7557","key":"10.1016\/j.phrs.2026.108330_bib61","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nature14508","article-title":"HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease","volume":"522","author":"Mirtschink","year":"2015","journal-title":"Nature"},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib62","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/ncb3338","article-title":"A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation","volume":"18","author":"Li","year":"2016","journal-title":"Nat. Cell. Biol."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib63","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.celrep.2019.08.100","article-title":"The RNA-Binding Protein A1CF Regulates Hepatic Fructose and Glycerol Metabolism via Alternative RNA Splicing","volume":"29","author":"Nikolaou","year":"2019","journal-title":"Cell. Rep."},{"key":"10.1016\/j.phrs.2026.108330_bib64","doi-asserted-by":"crossref","first-page":"566","DOI":"10.3389\/fcell.2020.00566","article-title":"Peroxisome-Deficiency and HIF-2\u03b1 Signaling Are Negative Regulators of Ketohexokinase Expression","volume":"8","author":"Eberhart","year":"2020","journal-title":"Front. Cell. Dev. Biol."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/19490976.2021.1900996","article-title":"Metagenomic analysis of mother-infant gut microbiome reveals global distinct and shared microbial signatures","volume":"13","author":"Wang","year":"2021","journal-title":"Gut Microbes"},{"key":"10.1016\/j.phrs.2026.108330_bib66","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbrc.2026.153358","article-title":"Medium-chain fatty acids activate fructose metabolism via up-regulating GLUT5-KHK axis","volume":"804","author":"Hou","year":"2026","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib67","doi-asserted-by":"crossref","first-page":"R499","DOI":"10.1152\/ajpregu.00128.2015","article-title":"Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK","volume":"309","author":"Patel","year":"2015","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib68","doi-asserted-by":"crossref","first-page":"G779","DOI":"10.1152\/ajpgi.00188.2015","article-title":"Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-\/- and GLUT5-\/- mice","volume":"309","author":"Patel","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib69","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.cmet.2017.12.016","article-title":"The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids","volume":"27","author":"Jang","year":"2018","journal-title":"Cell. Metab."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib70","doi-asserted-by":"crossref","first-page":"7126","DOI":"10.1096\/fj.201801526RR","article-title":"Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism","volume":"33","author":"Zhang","year":"2019","journal-title":"FASEB J."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib71","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1093\/jn\/nxaa113","article-title":"Cell-type-specific, ketohexokinase-dependent induction by fructose of lipogenic gene expression in mouse small intestine","volume":"150","author":"Al-Jawadi","year":"2020","journal-title":"J. Nutr."},{"issue":"7875","key":"10.1016\/j.phrs.2026.108330_bib72","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41586-021-03827-2","article-title":"Dietary fructose improves intestinal cell survival and nutrient absorption","volume":"597","author":"Taylor","year":"2021","journal-title":"Nature"},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib73","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1021\/acscentsci.5c00726","article-title":"Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261\/Ala226 to Preserve Intestinal Stem Cell Homeostasis","volume":"11","author":"Wu","year":"2025","journal-title":"ACS Cent. Sci."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib74","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cmet.2020.05.012","article-title":"Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction","volume":"32","author":"Andres-Hernando","year":"2020","journal-title":"Cell. Metab."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib75","article-title":"Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis","volume":"3","author":"Shepherd","year":"2020","journal-title":"JHEP Rep."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib76","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1038\/s42255-025-01402-x","article-title":"Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice","volume":"7","author":"Andres-Hernando","year":"2025","journal-title":"Nat. Metab."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib77","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1073\/pnas.1119908109","article-title":"Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice","volume":"109","author":"Ishimoto","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib78","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.26594","article-title":"High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase","volume":"58","author":"Ishimoto","year":"2013","journal-title":"Hepatology"},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib79","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1172\/JCI94427","article-title":"Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice","volume":"128","author":"Lanaspa","year":"2018","journal-title":"J. Clin. Invest."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib80","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s42255-020-0222-9","article-title":"The small intestine shields the liver from fructose-induced steatosis","volume":"2","author":"Jang","year":"2020","journal-title":"Nat. Metab."},{"issue":"23","key":"10.1016\/j.phrs.2026.108330_bib81","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.184396","article-title":"Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism","volume":"9","author":"Park","year":"2024","journal-title":"JCI Insight"},{"key":"10.1016\/j.phrs.2026.108330_bib82","doi-asserted-by":"crossref","DOI":"10.1016\/j.metabol.2023.155591","article-title":"Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD","volume":"145","author":"Park","year":"2023","journal-title":"Metabolism"},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib83","doi-asserted-by":"crossref","first-page":"G708","DOI":"10.1152\/ajpgi.00235.2025","article-title":"Beyond fructolysis: ketohexokinase orchestrates ER proteostasis in nutrient-stressed hepatocytes","volume":"329","author":"Elsaid","year":"2025","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"10.1016\/j.phrs.2026.108330_bib84","doi-asserted-by":"crossref","DOI":"10.1016\/j.molmet.2021.101196","article-title":"Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction","volume":"48","author":"Gutierrez","year":"2021","journal-title":"Mol. Metab."},{"issue":"22","key":"10.1016\/j.phrs.2026.108330_bib85","doi-asserted-by":"crossref","first-page":"13546","DOI":"10.1021\/acs.jmedchem.0c00944","article-title":"Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose","volume":"63","author":"Futatsugi","year":"2020","journal-title":"J. Med. Chem."},{"issue":"19","key":"10.1016\/j.phrs.2026.108330_bib86","doi-asserted-by":"crossref","first-page":"13501","DOI":"10.1021\/acs.jmedchem.3c00715","article-title":"Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease","volume":"66","author":"Zhu","year":"2023","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.phrs.2026.108330_bib87","doi-asserted-by":"crossref","unstructured":"Hong J.G., Carbajal Y., Trotman J., Glass M., Sclar V., Alter I.L., Zhang P., Wang L., Chen L., Petitjean M., Friedman S.L., DeRossi C., Chu J. Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism. bioRxiv [Preprint], 2024, 2024.01.17.576067.","DOI":"10.1101\/2024.01.17.576067"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib88","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1007\/s00210-025-04757-w","article-title":"Malvidin-3,5-O-diglucoside derived from spine grape (Vitis davidii) inhibits fructose-induced lipid accumulation in HepG2 cells: beneficial effects on MASLD treatment","volume":"399","author":"Cheng","year":"2026","journal-title":"Naunyn Schmiede Arch. Pharmacol."},{"issue":"30","key":"10.1016\/j.phrs.2026.108330_bib89","doi-asserted-by":"crossref","first-page":"18717","DOI":"10.1021\/acs.jafc.5c00716","article-title":"Malvidin-3-O-glucoside and Malvidin-3,5-O-diglucoside Alleviate Glycolipid Metabolic Disorder by Modulating Pancreas and Liver Functions and Gut Microbiota","volume":"73","author":"Yue","year":"2025","journal-title":"J. Agric. Food Chem."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib90","article-title":"Silico Analysis of Saroglitazar and Ferulic Acid Binding to Human Ketohexokinase: Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)","volume":"17","author":"Tiwari","year":"2025","journal-title":"Cureus"},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib91","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1159\/000343390","article-title":"Fructose acutely stimulates NHE3 activity in kidney proximal tubule","volume":"36","author":"Queiroz-Leite","year":"2012","journal-title":"Kidney Blood Press. Res."},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib92","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.3390\/nu10091244","article-title":"Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets","volume":"10","author":"Gonzalez-Vicente","year":"2018","journal-title":"Nutrients"},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib93","doi-asserted-by":"crossref","first-page":"885","DOI":"10.3390\/nu9080885","article-title":"Dietary Fructose Enhances the Ability of Low Concentrations of Angiotensin II to Stimulate Proximal Tubule Na\u207a Reabsorption","volume":"9","author":"Gonzalez-Vicente","year":"2017","journal-title":"Nutrients"},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib94","doi-asserted-by":"crossref","first-page":"F1513","DOI":"10.1152\/ajprenal.00543.2019","article-title":"Dietary fructose enhances angiotensin II-stimulated Na+ transport via activation of PKC-\u03b1 in renal proximal tubules","volume":"318","author":"Yang","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib95","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1161\/HYPERTENSIONAHA.113.02564","article-title":"Fructose stimulates Na\/H exchange activity and sensitizes the proximal tubule to angiotensin II","volume":"63","author":"Cabral","year":"2014","journal-title":"Hypertension"},{"key":"10.1016\/j.phrs.2026.108330_bib96","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jnutbio.2019.05.017","article-title":"Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase","volume":"71","author":"Hayasaki","year":"2019","journal-title":"J. Nutr. Biochem."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib97","doi-asserted-by":"crossref","first-page":"F1204","DOI":"10.1152\/ajprenal.00063.2004","article-title":"Effects of dietary fat, NaCl, and fructose on renal sodium and water transporter abundances and systemic blood pressure","volume":"287","author":"Song","year":"2004","journal-title":"Am. J. Physiol. Ren. Physiol."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib98","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.140848","article-title":"Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor","volume":"6","author":"Andres-Hernando","year":"2021","journal-title":"JCI Insight"},{"key":"10.1016\/j.phrs.2026.108330_bib99","doi-asserted-by":"crossref","DOI":"10.1155\/2018\/5459439","article-title":"A Higher Fructose Intake Is Associated with Greater Albuminuria in Subjects with Type 2 Diabetes Mellitus","volume":"2018","author":"G\u00f3mez-S\u00e1mano","year":"2018","journal-title":"Int. J. Nephrol."},{"issue":"10","key":"10.1016\/j.phrs.2026.108330_bib100","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0003431","article-title":"Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999-2004","volume":"3","author":"Shoham","year":"2008","journal-title":"PLoS. One"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib101","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1093\/ndt\/gfr223","article-title":"Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease","volume":"27","author":"Brymora","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib102","doi-asserted-by":"crossref","first-page":"F712","DOI":"10.1152\/ajprenal.00433.2009","article-title":"Dietary fructose causes tubulointerstitial injury in the normal rat kidney","volume":"298","author":"Nakayama","year":"2010","journal-title":"Am. J. Physiol. Ren. Physiol."},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib103","doi-asserted-by":"crossref","first-page":"F1256","DOI":"10.1152\/ajprenal.00181.2007","article-title":"Fructose, but not dextrose, accelerates the progression of chronic kidney disease","volume":"293","author":"Gersch","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib104","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1681\/ASN.2013080901","article-title":"Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy","volume":"25","author":"Lanaspa","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib105","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1681\/ASN.2008060576","article-title":"Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells","volume":"20","author":"Cirillo","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"10.1016\/j.phrs.2026.108330_bib106","doi-asserted-by":"crossref","DOI":"10.1016\/j.diabres.2021.109034","article-title":"Endogenous fructose is correlated with urinary albumin creatinine ratios and uric acid in type 2 diabetes mellitus","volume":"179","author":"Bian","year":"2021","journal-title":"Diabetes Res. Clin. Pract."},{"key":"10.1016\/j.phrs.2026.108330_bib107","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.metabol.2018.03.020","article-title":"Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice","volume":"85","author":"Doke","year":"2018","journal-title":"Metabolism"},{"key":"10.1016\/j.phrs.2026.108330_bib108","doi-asserted-by":"crossref","DOI":"10.1016\/j.cellsig.2021.110082","article-title":"IL-6\/STAT3 signaling activation exacerbates high fructose-induced podocyte hypertrophy by ketohexokinase-A-mediated tristetraprolin down-regulation","volume":"86","author":"Zhou","year":"2021","journal-title":"Cell. Signal."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib109","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/ki.2013.492","article-title":"Fructokinase activity mediates dehydration-induced renal injury","volume":"86","author":"Roncal Jimenez","year":"2014","journal-title":"Kidney Int."},{"issue":"4117","key":"10.1016\/j.phrs.2026.108330_bib110","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1126\/science.182.4117.1146","article-title":"Polyol accumulation in galactosemic and diabetic rats: control by an aldose reductase inhibitor","volume":"182","author":"Dvornik","year":"1973","journal-title":"Science"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib111","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/ki.2014.47","article-title":"Cyclical dehydration-induced renal injury and Mesoamerican nephropathy: as sweet by any other name?","volume":"86","author":"Robey","year":"2014","journal-title":"Kidney Int."},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib112","doi-asserted-by":"crossref","first-page":"F722","DOI":"10.1152\/ajprenal.00306.2016","article-title":"Aging-associated renal disease in mice is fructokinase dependent","volume":"311","author":"Roncal-Jimenez","year":"2016","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"10.1016\/j.phrs.2026.108330_bib113","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14181","article-title":"Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice","volume":"8","author":"Andres-Hernando","year":"2017","journal-title":"Nat. Commun."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib114","doi-asserted-by":"crossref","first-page":"508","DOI":"10.2337\/db14-0411","article-title":"Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway","volume":"64","author":"Marek","year":"2015","journal-title":"Diabetes"},{"key":"10.1016\/j.phrs.2026.108330_bib115","doi-asserted-by":"crossref","unstructured":"Lopez M.L., Kang T., Espeleta A., Rubtsova V.I., Baek J., Songcuan J., Moyer E.M., Kim J., Song W.S., Jung S., D'Sa N., Anica A., Tran E., Chun Y., Choi W., Jang K.H., Kelly M.E., Tamburini I.J., Alam Y.H., Le J., Ramirez C.B., Kataru R.P., Hong S.P., Nicholas D.A., Xue K.S., Lee G., Bae H., Jang C. Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling. bioRxiv [Preprint], 2025, 2025.08.18.670963.","DOI":"10.1101\/2025.08.18.670963"},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib116","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.vascn.2008.01.001","article-title":"Gene and protein expression changes in response to normoxic perfusion in mouse hearts","volume":"57","author":"Farag\u00f3","year":"2008","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"10.1016\/j.phrs.2026.108330_bib117","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.yjmcc.2025.02.005","article-title":"Hypoxic compound exercise improves cardiac function in Drosophila high fructose diet via KHK","volume":"201","author":"Ping","year":"2025","journal-title":"J. Mol. Cell. Cardiol."},{"key":"10.1016\/j.phrs.2026.108330_bib118","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jare.2021.10.007","article-title":"miR-155 down-regulation protects the heart from hypoxic damage by activating fructose metabolism in cardiac fibroblasts","volume":"39","author":"Zhang","year":"2022","journal-title":"J. Adv. Res."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib119","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1753-4887.2008.00037.x","article-title":"Effect of consuming different caloric sweeteners on bone health and possible mechanisms","volume":"66","author":"Tsanzi","year":"2008","journal-title":"Nutr. Rev."},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib120","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0093611","article-title":"Chronic high fructose intake reduces serum 1,25 (OH)2D3 levels in calcium-sufficient rodents","volume":"9","author":"Douard","year":"2014","journal-title":"PLoS. One"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib121","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s00223-004-0274-y","article-title":"Soft drink and milk consumption, physical activity, bone mass, and upper limb fractures in children: a population-based case-control study","volume":"75","author":"Ma","year":"2004","journal-title":"Calcif. Tissue Int."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib122","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/1054-139X(94)90506-1","article-title":"Carbonated beverages, dietary calcium, the dietary calcium\/phosphorus ratio, and bone fractures in girls and boys","volume":"15","author":"Wyshak","year":"1994","journal-title":"J. Adolesc. Health"},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib123","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00223-020-00663-w","article-title":"Bone Growth is Influenced by Fructose in Adolescent Male Mice Lacking Ketohexokinase (KHK)","volume":"106","author":"Williams","year":"2020","journal-title":"Calcif. Tissue Int."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib124","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1177\/0271678X15606719","article-title":"Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity","volume":"36","author":"Agrawal","year":"2016","journal-title":"J. Cereb. Blood Flow. Metab."},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib125","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1007\/s12035-017-0518-2","article-title":"Short-Term Fructose Feeding Induces Inflammation and Oxidative Stress in the Hippocampus of Young and Adult Rats","volume":"55","author":"Cigliano","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"10.1016\/j.phrs.2026.108330_bib126","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.bbi.2018.05.018","article-title":"High-fructose diet during adolescent development increases neuroinflammation and depressive-like behavior without exacerbating outcomes after stroke","volume":"73","author":"Harrell","year":"2018","journal-title":"Brain Behav. Immun."},{"issue":"5","key":"10.1016\/j.phrs.2026.108330_bib127","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbadis.2020.166036","article-title":"Dietary fructose as a model to explore the influence of peripheral metabolism on brain function and plasticity","volume":"1867","author":"Gomez-Pinilla","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib128","article-title":"The impact of high-sugar diets on central nervous system disorders: mechanisms, pathogenesis, and dietary implication","volume":"57","author":"Li","year":"2025","journal-title":"Ann. Med."},{"key":"10.1016\/j.phrs.2026.108330_bib129","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.brainres.2016.12.022","article-title":"Specific regions of the brain are capable of fructose metabolism","volume":"1657","author":"Oppelt","year":"2017","journal-title":"Brain Res."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib130","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/14734220601064759","article-title":"Fructose metabolism in the cerebellum","volume":"6","author":"Funari","year":"2007","journal-title":"Cerebellum"},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib131","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bbadis.2017.10.012","article-title":"Short-term fructose ingestion affects the brain independently from establishment of metabolic syndrome","volume":"1864","author":"Jim\u00e9nez-Maldonado","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib132","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1038\/s12276-023-01112-y","article-title":"Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction","volume":"55","author":"Li","year":"2023","journal-title":"Exp. Mol. Med."},{"issue":"14","key":"10.1016\/j.phrs.2026.108330_bib133","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abm7985","article-title":"Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging","volume":"8","author":"Tee","year":"2022","journal-title":"Sci. Adv."},{"key":"10.1016\/j.phrs.2026.108330_bib134","doi-asserted-by":"crossref","DOI":"10.1016\/j.canlet.2022.215617","article-title":"GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer","volume":"534","author":"Shen","year":"2022","journal-title":"Cancer Lett."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib135","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1016\/j.apsb.2024.04.024","article-title":"KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2","volume":"14","author":"Peng","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib136","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1136\/gutjnl-2021-326299","article-title":"Genetically proxied ketohexokinase function and risk of colorectal cancer: a Mendelian randomisation study","volume":"72","author":"Buziau","year":"2023","journal-title":"Gut"},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib137","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/s12276-023-01153-3","article-title":"The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer","volume":"56","author":"Kang","year":"2024","journal-title":"Exp. Mol. Med."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib138","doi-asserted-by":"crossref","DOI":"10.1016\/j.yexcr.2024.114038","article-title":"Ketohexokinase-A deficiency attenuates the proliferation via reducing \u03b2-catenin in gastric cancer cells","volume":"438","author":"Ma","year":"2024","journal-title":"Exp. Cell. Res."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib139","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ajg.2020.08.007","article-title":"KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1","volume":"22","author":"Yang","year":"2021","journal-title":"Arab. J. Gastroenterol."},{"issue":"2","key":"10.1016\/j.phrs.2026.108330_bib140","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1007\/s13577-022-00677-6","article-title":"USP36 promotes tumor growth of non-small cell lung cancer via increasing KHK-A expression by regulating c-MYC-hnRNPH1\/H2 axis","volume":"35","author":"Deng","year":"2022","journal-title":"Hum. Cell."},{"key":"10.1016\/j.phrs.2026.108330_bib141","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.3389\/fonc.2019.01123","article-title":"Prognostic Impact of Metabolism Reprogramming Markers Acetyl-CoA Synthetase 2 Phosphorylation and Ketohexokinase-A Expression in Non-Small-Cell Lung Carcinoma","volume":"9","author":"Yang","year":"2019","journal-title":"Front. Oncol."},{"issue":"3","key":"10.1016\/j.phrs.2026.108330_bib142","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.bbrc.2018.07.040","article-title":"Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma","volume":"503","author":"Gao","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib143","doi-asserted-by":"crossref","first-page":"5436","DOI":"10.1038\/s41467-020-19263-1","article-title":"Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer","volume":"11","author":"Kim","year":"2020","journal-title":"Nat. Commun."},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib144","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2023.107368","article-title":"Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development","volume":"26","author":"Guccini","year":"2023","journal-title":"iScience"},{"issue":"4","key":"10.1016\/j.phrs.2026.108330_bib145","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aav4570","article-title":"The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62","volume":"5","author":"Xu","year":"2019","journal-title":"Sci. Adv."},{"issue":"8","key":"10.1016\/j.phrs.2026.108330_bib146","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1158\/0008-5472.CAN-22-1844","article-title":"Fructose metabolism in tumor endothelial cells promotes angiogenesis by activating AMPK signaling and mitochondrial respiration","volume":"83","author":"Fang","year":"2023","journal-title":"Cancer Res."},{"issue":"8043","key":"10.1016\/j.phrs.2026.108330_bib147","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/s41586-024-08258-3","article-title":"Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer","volume":"636","author":"Fowle-Grider","year":"2024","journal-title":"Nature"},{"issue":"11","key":"10.1016\/j.phrs.2026.108330_bib148","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.7150\/ijms.108549","article-title":"Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications","volume":"22","author":"Chen","year":"2025","journal-title":"Int. J. Med. Sci."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib149","first-page":"501","article-title":"The Discovery of GS-1291269: a neutral ketohexokinase (KHK) inhibitor with an unusual thietane amine functional group","volume":"69","author":"Kasun","year":"2026","journal-title":"J. Med. Chem."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib150","doi-asserted-by":"crossref","DOI":"10.1111\/cts.13644","article-title":"Study of the ketohexokinase inhibitor PF-06835919 as a clinical cytochrome P450 3A inducer: integrated use of oral midazolam and liquid biopsy","volume":"17","author":"Qiu","year":"2024","journal-title":"Clin. Transl. Sci."},{"issue":"9","key":"10.1016\/j.phrs.2026.108330_bib151","doi-asserted-by":"crossref","DOI":"10.1124\/dmd.122.000953","article-title":"Transporter-enzyme interplay in the pharmacokinetics of PF-06835919, a first-in-class ketohexokinase inhibitor for metabolic disorders and non-alcoholic fatty liver disease","volume":"50","author":"Weng","year":"2022","journal-title":"Drug. Metab. Dispos."},{"issue":"7","key":"10.1016\/j.phrs.2026.108330_bib152","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1021\/ml200070g","article-title":"Inhibitors of ketohexokinase: discovery of pyrimidinopyrimidines with specific substitution that complements the ATP-binding site","volume":"2","author":"Maryanoff","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"issue":"6","key":"10.1016\/j.phrs.2026.108330_bib153","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0157458","article-title":"Bioactivity-guided identification of botanical inhibitors of ketohexokinase","volume":"11","author":"Le","year":"2016","journal-title":"PLoS. One"},{"issue":"18","key":"10.1016\/j.phrs.2026.108330_bib154","doi-asserted-by":"crossref","first-page":"7835","DOI":"10.1021\/acs.jmedchem.7b00947","article-title":"Discovery of fragment-derived small molecules for in vivo inhibition of ketohexokinase (KHK)","volume":"60","author":"Huard","year":"2017","journal-title":"J. Med. Chem."},{"issue":"23","key":"10.1016\/j.phrs.2026.108330_bib155","doi-asserted-by":"crossref","first-page":"15960","DOI":"10.1021\/acs.jmedchem.3c01410","article-title":"Identification of LY3522348: a highly selective and orally efficacious ketohexokinase inhibitor","volume":"66","author":"Durham","year":"2023","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.phrs.2026.108330_bib156","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmcl.2024.129930","article-title":"Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability","volume":"112","author":"Heine","year":"2024","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"1","key":"10.1016\/j.phrs.2026.108330_bib157","first-page":"126","article-title":"Examining prenylated xanthones as potential inhibitors against ketohexokinase C isoform for the treatment of fructose-driven metabolic disorders: an integrated computational approach","volume":"18","author":"Elsaman","year":"2025","journal-title":"Pharm. (Basel)"},{"key":"10.1016\/j.phrs.2026.108330_bib158","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2025.1531512","article-title":"Pharmacophore-based virtual screening and in silico investigations of small molecule library for discovery of human hepatic ketohexokinase inhibitors for the treatment of fructose metabolic disorders","volume":"16","author":"Elsaman","year":"2025","journal-title":"Front. Pharmacol."}],"container-title":["Pharmacological Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1043661826002458?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1043661826002458?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T14:06:11Z","timestamp":1785074771000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1043661826002458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":158,"alternative-id":["S1043661826002458"],"URL":"https:\/\/doi.org\/10.1016\/j.phrs.2026.108330","relation":{},"ISSN":["1043-6618"],"issn-type":[{"value":"1043-6618","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Ketohexokinase: A central mediator of fructose-associated pathogenesis and promising therapeutic target","name":"articletitle","label":"Article Title"},{"value":"Pharmacological Research","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.phrs.2026.108330","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"108330"}}