{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:46:52Z","timestamp":1791859612166,"version":"4.3.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"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. Pharmacol."],"abstract":"<jats:p>Metabolic and alcohol-related liver disease (MetALD), characterized by excessive alcohol intake in individuals with metabolic dysfunction, is a growing health burden worldwide. Hepatic macrophages play a pivotal role in MetALD pathogenesis, with pro-inflammatory infiltrating monocytes\/macrophages contributing to liver injury. Fucoidan, a sulfated polysaccharide derived from brown algae, is known for its anti-inflammatory properties, yet its intracellular targets remain poorly defined. Here, we identify prolyl hydroxylase domain-containing protein 2 (PHD2) as a novel intracellular binding partner of fucoidan. Using a high-fat diet plus ethanol-induced MetALD mouse model, we demonstrate that fucoidan significantly attenuates hepatocyte injury, steatosis, and peripheral monocyte infiltration in a dose-dependent manner. <jats:italic>In vitro<\/jats:italic>, fucoidan markedly suppressed ethanol- and LPS-induced THP-1 monocyte migration. Mechanistically, we show that fucoidan binds directly to PHD2, enhancing proteasome-mediated ubiquitination and degradation of HIF-1\u03b1, a key transcription factor driving monocyte recruitment and inflammation. Our findings reveal a previously unrecognized mechanism by which fucoidan exerts its anti-inflammatory effects via targeting the PHD2\u2013HIF-1\u03b1 axis, offering a promising therapeutic strategy for MetALD.<\/jats:p>","DOI":"10.3389\/fphar.2025.1617175","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:28:55Z","timestamp":1755235735000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Fucoidan from Fucus vesiculosus alleviates MetALD via promoting HIF-1\u03b1 ubiquitination to suppress peripheral monocyte infiltration"],"prefix":"10.3389","volume":"16","author":[{"given":"Lei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialiang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohui","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daming","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"230115691","DOI":"10.1016\/j.carbpol.2019.115691","article-title":"Immunomodulatory properties of photopolymerizable fucoidan and carrageenans","volume":"230","author":"Amin","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.3390\/molecules25051087","article-title":"Study on absorption mechanism and tissue distribution of fucoidan","volume":"25","author":"Bai","year":"2020","journal-title":"Molecules"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4082","DOI":"10.1093\/emboj\/cdg392","article-title":"HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia","volume":"22","author":"Berra","year":"2003","journal-title":"Embo J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nprot.2013.032","article-title":"Mouse model of chronic and binge ethanol feeding (the NIAAA model)","volume":"8","author":"Bertola","year":"2013","journal-title":"Nat. Protoc."},{"key":"B5","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/jsfa.2740040205","article-title":"Manufacture of algal chemicals. VI.\u2014Laboratory-scale isolation of l-fucose from brown marine algae","volume":"4","author":"Black","year":"1953","journal-title":"J. Sci. Food Agric."},{"key":"B6","doi-asserted-by":"publisher","first-page":"249","DOI":"10.3390\/md16080249","article-title":"Phycochemical constituents and biological activities of fucus spp","volume":"16","author":"Catarino","year":"2018","journal-title":"Mar. Drugs"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4436","DOI":"10.3390\/md13074436","article-title":"Low molecular weight fucoidan inhibits tumor angiogenesis through downregulation of HIF-1\/VEGF signaling under hypoxia","volume":"13","author":"Chen","year":"2015","journal-title":"Mar. Drugs"},{"key":"B8","doi-asserted-by":"publisher","first-page":"72676","DOI":"10.18632\/oncotarget.20243","article-title":"Inhibiting PHD2 in bone marrow mesenchymal stem cells via lentiviral vector-mediated RNA interference facilitates the repair of periodontal tissue defects in SD rats","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"B9","doi-asserted-by":"publisher","first-page":"131111791","DOI":"10.1016\/j.intimp.2024.111791","article-title":"Dexamethasone protects against asthma via regulating Hif-1\u03b1-glycolysis-lactate axis and protein lactylation","volume":"131","author":"Chen","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"64344","DOI":"10.1016\/j.fct.2013.12.009","article-title":"AKT signaling is involved in fucoidan-induced inhibition of growth and migration of human bladder cancer cells","volume":"64","author":"Cho","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3390\/md17080458","article-title":"Possibilities of fucoidan utilization in the development of pharmaceutical dosage forms","volume":"17","author":"Citkowska","year":"2019","journal-title":"Mar. Drugs"},{"key":"B12","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/s0092-8674(03)00154-5","article-title":"HIF-1alpha is essential for myeloid cell-mediated inflammation","volume":"112","author":"Cramer","year":"2003","journal-title":"Cell."},{"key":"B13","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1172\/jci22675","article-title":"Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair","volume":"115","author":"Duffield","year":"2005","journal-title":"J. Clin. Investig."},{"key":"B14","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.jid.2019.06.143","article-title":"LRG1 promotes keratinocyte migration and wound repair through regulation of HIF-1\u03b1 stability","volume":"140","author":"Gao","year":"2020","journal-title":"J. Investig. Dermatol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"167105513","DOI":"10.1016\/j.phrs.2021.105513","article-title":"Suppression of macrophage migration by down-regulating Src\/FAK\/P130Cas activation contributed to the anti-inflammatory activity of sinomenine","volume":"167","author":"Gao","year":"2021","journal-title":"Pharmacol. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","article-title":"Hepatic inflammatory responses in liver fibrosis","volume":"20","author":"Hammerich","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"153248","DOI":"10.1016\/j.ijbiomac.2020.02.315","article-title":"An insight into anti-inflammatory effects of natural polysaccharides","volume":"153","author":"Hou","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1093\/carcin\/bgs396","article-title":"Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGF\u03b2 receptor degradation in breast cancer","volume":"34","author":"Hsu","year":"2013","journal-title":"Carcinogenesis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1358\/mf.2005.27.10.948919","article-title":"A quantitative method to detect fucoidan in human plasma using a novel antibody","volume":"27","author":"Irhimeh","year":"2005","journal-title":"Methods Find. Exp. Clin. Pharmacol."},{"key":"B20","first-page":"251","article-title":"Macrophages and alcohol-related liver inflammation","volume":"37","author":"Ju","year":"2015","journal-title":"Alcohol Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/hep.22950","article-title":"Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis","volume":"50","author":"Karlmark","year":"2009","journal-title":"Hepatology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1002\/hep.23894","article-title":"The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes","volume":"52","author":"Karlmark","year":"2010","journal-title":"Hepatology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"91","DOI":"10.14740\/gr1517","article-title":"Trends and outcomes of alcoholic liver cirrhosis hospitalizations in the last two decades: analysis of the nationwide inpatient sample","volume":"15","author":"Laswi","year":"2022","journal-title":"Gastroenterol. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.3390\/molecules13081671","article-title":"Fucoidan: structure and bioactivity","volume":"13","author":"Li","year":"2008","journal-title":"Molecules"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.3390\/md13021051","article-title":"Fucoidan from fucus vesiculosus protects against alcohol-induced liver damage by modulating inflammatory mediators in mice and HepG2 cells","volume":"13","author":"Lim","year":"2015","journal-title":"Mar. Drugs"},{"key":"B26","doi-asserted-by":"publisher","first-page":"4670","DOI":"10.1096\/fj.201701139R","article-title":"Hepatic PHD2\/HIF-1\u03b1 axis is involved in postexercise systemic energy homeostasis","volume":"32","author":"Luo","year":"2018","journal-title":"Faseb J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"154113602","DOI":"10.1016\/j.biopha.2022.113602","article-title":"Fucoidan inhibits EGFR redistribution and potentiates sorafenib to overcome sorafenib-resistant hepatocellular carcinoma","volume":"154","author":"Luo","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B28","doi-asserted-by":"publisher","first-page":"133106453","DOI":"10.1016\/j.jfca.2024.106453","article-title":"Seaweed bioactives potential as nutraceuticals and functional ingredients: a review","volume":"133","author":"Matos","year":"2024","journal-title":"J. Food Compos. Analysis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3389\/fmars.2016.00129","article-title":"Fucoidans from brown alga fucus evanescens: structure and biological activity","volume":"3","author":"Menshova","year":"2016","journal-title":"Front. Mar. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"48","DOI":"10.3390\/md13010048","article-title":"Intestinal absorption of fucoidan extracted from the brown seaweed, Cladosiphon okamuranus","volume":"13","author":"Nagamine","year":"2014","journal-title":"Mar. Drugs"},{"key":"B31","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3390\/md20030193","article-title":"The biochemical composition and antioxidant properties of fucus vesiculosus from the arctic region","volume":"20","author":"Obluchinskaya","year":"2022","journal-title":"Mar. Drugs"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.3390\/plants12122380","article-title":"Arctic edible brown alga fucus distichus L.: biochemical composition, antiradical potential and human health risk","volume":"12","author":"Obluchinskaya","year":"2023","journal-title":"Plants (Basel)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1097\/hep.0000000000000914","article-title":"Waitlisting and liver transplantation for MetALD in the United States: an analysis of the UNOS national registry","volume":"81","author":"Ochoa-Allemant","year":"2025","journal-title":"Hepatology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.immuni.2014.09.008","article-title":"HIF transcription factors, inflammation, and immunity","volume":"41","author":"Palazon","year":"2014","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1002\/ptr.3140","article-title":"The differential effect of high and low molecular weight fucoidans on the severity of collagen-induced arthritis in mice","volume":"24","author":"Park","year":"2010","journal-title":"Phytother. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"132","DOI":"10.3390\/md16040132","article-title":"Pharmacokinetic and tissue distribution of fucoidan from fucus vesiculosus after oral administration to rats","volume":"16","author":"Pozharitskaya","year":"2018","journal-title":"Mar. Drugs"},{"key":"B38","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1097\/hep.0000000000000976","article-title":"Exploring the role of macrophages in the pathogenesis of alcohol-associated liver disease","volume":"81","author":"Ramachandran","year":"2025","journal-title":"Hepatology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"14259","DOI":"10.2147\/ceg.S299775","article-title":"Diminished non-classical monocytes in the blood associate with disease severity in alcoholic hepatitis","volume":"14","author":"Rasmussen","year":"2021","journal-title":"Clin. Exp. Gastroenterol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1097\/hep.0000000000000520","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1097\/hep.0000000000000918","article-title":"Kupffer cell diversity maintains liver function in alcohol-associated liver disease","volume":"81","author":"Sasaki","year":"2025","journal-title":"Hepatology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"711635","DOI":"10.1038\/ncomms11635","article-title":"HIF-1\u03b1-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity","volume":"7","author":"Semba","year":"2016","journal-title":"Nat. Commun."},{"key":"B43","doi-asserted-by":"publisher","first-page":"cm8","DOI":"10.1126\/stke.4072007cm8","article-title":"Hypoxia-inducible factor 1 (HIF-1) pathway","volume":"2007","author":"Semenza","year":"2007","journal-title":"Sci. STKE"},{"key":"B44","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-inducible factors in physiology and medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell."},{"key":"B45","doi-asserted-by":"publisher","first-page":"221623","DOI":"10.1016\/j.ijbiomac.2022.09.047","article-title":"Fucoidan from sargassum hemiphyllum inhibits the stemness of cancer stem cells and epithelial-mesenchymal transitions in bladder cancer cells","volume":"221","author":"Sung","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1053\/j.gastro.2014.10.042","article-title":"Gut-liver axis in alcoholic liver disease","volume":"148","author":"Szabo","year":"2015","journal-title":"Gastroenterology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"S27","DOI":"10.1186\/1755-1536-5-s1-s27","article-title":"Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo","volume":"5","author":"Tacke","year":"2012","journal-title":"Fibrogenes. Tissue Repair"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1016\/j.jhep.2017.02.026","article-title":"Targeting hepatic macrophages to treat liver diseases","volume":"66","author":"Tacke","year":"2017","journal-title":"J. Hepatol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.jhep.2017.11.010","article-title":"Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil-mediated complement activation","volume":"68","author":"Tang","year":"2018","journal-title":"J. Hepatol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"G605","DOI":"10.1152\/ajpgi.1998.275.4.G605","article-title":"II. Alcoholic liver injury involves activation of kupffer cells by endotoxin","volume":"275","author":"Thurman","year":"1998","journal-title":"Am. J. Physiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1189\/jlb.6A0114-004RR","article-title":"Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice","volume":"96","author":"Wang","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"302","DOI":"10.3390\/md21050302","article-title":"Fucoidan from fucus vesiculosus inhibits inflammatory response, both in vitro and in vivo","volume":"21","author":"Wang","year":"2023","journal-title":"Mar. Drugs"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1111\/acer.12782","article-title":"Ethanol promotes cell migration via activation of chloride channels in nasopharyngeal carcinoma cells","volume":"39","author":"Wei","year":"2015","journal-title":"Alcohol Clin. Exp. Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41423-020-00558-8","article-title":"Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities","volume":"18","author":"Wen","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1002\/hep.32612","article-title":"Macrophage-derived MLKL in alcohol-associated liver disease: regulation of phagocytosis","volume":"77","author":"Wu","year":"2023","journal-title":"Hepatology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1111\/hepr.14133","article-title":"Distinct characteristics of MetALD (Metabolic dysfunction-associated steatotic liver disease with greater alcohol consumption) in the general population","volume":"55","author":"Yoon","year":"2025","journal-title":"Hepatol. Res."},{"key":"B58","doi-asserted-by":"publisher","first-page":"77183","DOI":"10.1016\/j.freeradbiomed.2014.08.030","article-title":"Binge alcohol promotes hypoxic liver injury through a CYP2E1-HIF-1\u03b1-dependent apoptosis pathway in mice and humans","volume":"77","author":"Yun","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"B59","doi-asserted-by":"publisher","first-page":"3842","DOI":"10.1039\/d0fo03220d","article-title":"Protective effects of fucoidan against ethanol-induced liver injury through maintaining mitochondrial function and mitophagy balance in rats","volume":"12","author":"Zhao","year":"2021","journal-title":"Food Funct."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e11049","DOI":"10.1371\/journal.pone.0011049","article-title":"Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis","volume":"5","author":"Zimmermann","year":"2010","journal-title":"PLoS One"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1617175\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:28:56Z","timestamp":1755235736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1617175\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":59,"alternative-id":["10.3389\/fphar.2025.1617175"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1617175","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"article-number":"1617175"}}