{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:55:41Z","timestamp":1789052141674,"version":"build-2803163510"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371425"],"award-info":[{"award-number":["82371425"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2022MH018"],"award-info":[{"award-number":["ZR2022MH018"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biomed"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Iron overload-related liver injury is a major clinical problem in hereditary hemochromatosis, transfusional siderosis, and chronic liver diseases, yet current treatments such as iron chelation therapy and phlebotomy are limited by safety and efficacy issues. Cannabinoid receptor type 2 (CB2R) has been implicated in the regulation of iron metabolism, but its role and underlying mechanism in iron overload remain unclear. Here, we investigated whether CB2R can prevent liver damage caused by iron overload and explored its potential mechanism. Male C57BL\/6J mice received 100 mg\/kg iron-dextran intraperitoneally to establish an iron overload model. Liver damage and iron deposition were evaluated via histology, serum biochemistry, and molecular analyses. Further studies using primary hepatocytes and Kupffer cells exposed to ferric ammonium citrate (FAC) were performed to explore cell type-specific mechanisms in vitro. Pharmacological CB2R activation with the selective agonist JWH133 reduced liver iron deposition, oxidative stress, and inflammation, whereas CB2R-knockout (KO) exacerbated these phenotypes. Mechanistically, CB2R activation suppressed signal transducer and activator of transcription 3 (STAT3)-dependent hepcidin transcription in hepatocytes, thereby enhancing ferroportin 1 (FPN1)-mediated iron efflux. Concurrently, CB2R promoted nuclear factor erythroid 2-related factor 2 (Nrf2)\/FPN1 signaling in Kupffer cells, decreasing the labile iron pool. These findings identify CB2R as a key regulator of hepatic iron homeostasis and suggest that targeting CB2R may offer a novel therapeutic strategy for iron overload-related diseases.<\/jats:p>","DOI":"10.1186\/s43556-026-00541-1","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:32:18Z","timestamp":1786325538000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activating Cannabinoid receptor 2 alleviates iron overload-induced liver damage via dual modulation of STAT3\/hepcidin and Nrf2\/FPN1 pathways"],"prefix":"10.1186","volume":"7","author":[{"given":"Han","family":"Deng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqian","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjie","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zegang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"541_CR1","doi-asserted-by":"publisher","unstructured":"Nemeth E, Ganz T. Hepcidin and Iron in Health and Disease. Annu Rev Med. 2023;74:261\u2013277. https:\/\/doi.org\/10.1146\/annurev-med-043021-032816.","DOI":"10.1146\/annurev-med-043021-032816"},{"issue":"8","key":"541_CR2","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1002\/hep4.2012","volume":"6","author":"CC Hsu","year":"2022","unstructured":"Hsu CC, Senussi NH, Fertrin KY, Kowdley KV. Iron overload disorders. Hepatol Commun. 2022;6(8):1842\u201354. https:\/\/doi.org\/10.1002\/hep4.2012.","journal-title":"Hepatol Commun"},{"issue":"2","key":"541_CR3","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1002\/hep.32270","volume":"76","author":"H Xiong","year":"2022","unstructured":"Xiong H, Zhang C, Han L, Xu T, Saeed K, Han J, et al. Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity. Hepatology. 2022;76(2):387\u2013403. https:\/\/doi.org\/10.1002\/hep.32270.","journal-title":"Hepatology"},{"issue":"1","key":"541_CR4","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1182\/blood-2018-06-815894","volume":"133","author":"CY Wang","year":"2019","unstructured":"Wang CY, Babitt JL. Liver iron sensing and body iron homeostasis. Blood. 2019;133(1):18\u201329. https:\/\/doi.org\/10.1182\/blood-2018-06-815894.","journal-title":"Blood"},{"key":"541_CR5","doi-asserted-by":"publisher","unstructured":"Zhang H, Shi H, Li X, Zhou S, Song X, Ma N, et al. Quercetin alleviates LPS\/iE-DAP-induced liver injury by suppressing ferroptosis via regulating ferritinophagy and intracellular iron efflux. Redox Biol. 2025;81(103557. https:\/\/doi.org\/10.1016\/j.redox.2025.103557.","DOI":"10.1016\/j.redox.2025.103557"},{"key":"541_CR6","doi-asserted-by":"publisher","unstructured":"Li Y, Qin M, Zhong W, Liu C, Deng G, Yang M, et al. RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease. Redox Biol. 2023;59:102559. https:\/\/doi.org\/10.1016\/j.redox.2022.102559","DOI":"10.1016\/j.redox.2022.102559"},{"issue":"1","key":"541_CR7","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-025-01102-4","volume":"20","author":"W Ge","year":"2025","unstructured":"Ge W, Liu X, Hu X, Yang Y, Chen H, Zhan-Mu O, et al. Electroacupuncture exerts antipruritic and anti-inflammatory effects on atopic dermatitis by activating CB2 receptor. Chin Med. 2025;20(1):72. https:\/\/doi.org\/10.1186\/s13020-025-01102-4.","journal-title":"Chin Med"},{"key":"541_CR8","doi-asserted-by":"publisher","unstructured":"Jia Y, Deng H, Qin Q, and Ma Z. JWH133 inhibits MPP(+)-induced inflammatory response and iron influx in astrocytes. Neurosci Lett. 2020;720:134779. https:\/\/doi.org\/10.1016\/j.neulet.2020.134779.","DOI":"10.1016\/j.neulet.2020.134779"},{"key":"541_CR9","doi-asserted-by":"publisher","unstructured":"Scandiffio R, Bonzano S, Cottone E, Shrestha S, Bossi S, De Marchis S, et al. Beta-caryophyllene modifies intracellular lipid composition in a cell model of hepatic steatosis by acting through CB2 and PPAR receptors. Int J Mol Sci. 2023. https:\/\/doi.org\/10.3390\/ijms24076060.","DOI":"10.3390\/ijms24076060"},{"issue":"7","key":"541_CR10","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1038\/s41401-022-01037-8","volume":"44","author":"SL Cai","year":"2023","unstructured":"Cai SL, Fan XG, Wu J, Wang Y, Hu XW, Pei SY, et al. CB2R agonist GW405833 alleviates acute liver failure in mice via inhibiting HIF-1\u03b1-mediated reprogramming of glycometabolism and macrophage proliferation. Acta Pharmacol Sin. 2023;44(7):1391\u2013403. https:\/\/doi.org\/10.1038\/s41401-022-01037-8.","journal-title":"Acta Pharmacol Sin"},{"key":"541_CR11","doi-asserted-by":"publisher","unstructured":"Wang HQ, Wan Z, Zhang Q, Su T, Yu D, Wang F, et al. Schisandrin B targets cannabinoid 2 receptor in Kupffer cell to ameliorate CCl(4)-induced liver fibrosis by suppressing NF-\u03baB and p38 MAPK pathway. Phytomedicine. 2022;98:153960. https:\/\/doi.org\/10.1016\/j.phymed.2022.153960.","DOI":"10.1016\/j.phymed.2022.153960"},{"key":"541_CR12","doi-asserted-by":"publisher","DOI":"10.1177\/20587384211035251","volume":"35","author":"Y Wu","year":"2021","unstructured":"Wu Y, Ma R, Long C, Shu Y, He P, Zhou Y, et al. The protective effect of cannabinoid type II receptor agonist AM1241 on ConA-induced liver injury in mice via mitogen-activated protein kinase signalling pathway. Int J Immunopathol Pharmacol. 2021;35:20587384211035251. https:\/\/doi.org\/10.1177\/20587384211035251.","journal-title":"Int J Immunopathol Pharmacol"},{"key":"541_CR13","doi-asserted-by":"publisher","unstructured":"Ali AM, El-Tawil OS, Al-Mokaddem AK, and Abd El-Rahman SS. Promoted inhibition of TLR4\/miR-155\/ NF(k)B p65 signaling by cannabinoid receptor 2 agonist (AM1241), aborts inflammation and progress of hepatic fibrosis induced by thioacetamide. Chem Biol Interact. 2021;336:109398. https:\/\/doi.org\/10.1016\/j.cbi.2021.109398.","DOI":"10.1016\/j.cbi.2021.109398"},{"issue":"22","key":"541_CR14","doi-asserted-by":"publisher","first-page":"4243","DOI":"10.1042\/bcj20160674","volume":"473","author":"YA Seo","year":"2016","unstructured":"Seo YA, Kumara R, Wetli H, Wessling-Resnick M. Regulation of divalent metal transporter-1 by serine phosphorylation. Biochem J. 2016;473(22):4243\u201354. https:\/\/doi.org\/10.1042\/bcj20160674.","journal-title":"Biochem J"},{"issue":"3","key":"541_CR15","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1152\/jn.00137.2024","volume":"132","author":"M Liu","year":"2024","unstructured":"Liu M, Pan D, Wang M, Deng H, Ma Z. JWH133 attenuates behavior deficits and iron accumulation in 6-OHDA-induced Parkinson\u2019s disease model rats. J Neurophysiol. 2024;132(3):733\u201343. https:\/\/doi.org\/10.1152\/jn.00137.2024.","journal-title":"J Neurophysiol"},{"issue":"8","key":"541_CR16","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1093\/ibd\/izac073","volume":"28","author":"C Tortora","year":"2022","unstructured":"Tortora C, Di Paola A, Creoli M, Argenziano M, Martinelli M, Miele E, et al. Effects of CB2 and TRPV1 stimulation on osteoclast overactivity induced by iron in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2022;28(8):1244\u201353. https:\/\/doi.org\/10.1093\/ibd\/izac073.","journal-title":"Inflamm Bowel Dis"},{"key":"541_CR17","doi-asserted-by":"publisher","unstructured":"Creoli M, Di Paola A, Tarallo A, Aziz S, Miele E, Martinelli M, et al. Effects of CB2 receptor modulation on macrophage polarization in pediatric inflammatory bowel disease. Int J Mol Sci. 2025. https:\/\/doi.org\/10.3390\/ijms26083720.","DOI":"10.3390\/ijms26083720"},{"key":"541_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2025.109888","author":"A Catapano","year":"2025","unstructured":"Catapano A, Cimmino F, Petrella L, Pizzella A, D\u2019angelo M, Ambrosio K, et al. Iron metabolism and ferroptosis in health and diseases: the crucial role of mitochondria in meta-bolically active tissues. J Nutr Biochem. 2025. https:\/\/doi.org\/10.1016\/j.jnutbio.2025.109888.","journal-title":"J Nutr Biochem"},{"key":"541_CR19","doi-asserted-by":"publisher","unstructured":"Nemeth E, Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci. 2021. https:\/\/doi.org\/10.3390\/ijms22126493.","DOI":"10.3390\/ijms22126493"},{"issue":"2","key":"541_CR20","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3324\/haematol.2019.232124","volume":"105","author":"C Camaschella","year":"2020","unstructured":"Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica. 2020;105(2):260\u201372. https:\/\/doi.org\/10.3324\/haematol.2019.232124.","journal-title":"Haematologica"},{"issue":"10","key":"541_CR21","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1002\/mnfr.201600197","volume":"60","author":"R Kamikubo","year":"2016","unstructured":"Kamikubo R, Kai K, Tsuji-Naito K, Akagawa M. \u03b2-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016;60(10):2228\u201342. https:\/\/doi.org\/10.1002\/mnfr.201600197.","journal-title":"Mol Nutr Food Res"},{"issue":"10","key":"541_CR22","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1002\/hep4.1415","volume":"3","author":"HM Wu","year":"2019","unstructured":"Wu HM, Kim TH, Kim A, Koo JH, Joo MS, Kim SG. Liver X Receptor \u03b1-Induced Cannabinoid Receptor 2 Inhibits Ubiquitin-Specific Peptidase 4 Through miR-27b. Protecting Hepatocytes From TGF-\u03b2 Hepatol Commun. 2019;3(10):1373\u201387. https:\/\/doi.org\/10.1002\/hep4.1415.","journal-title":"Protecting Hepatocytes From TGF-\u03b2 Hepatol Commun"},{"key":"541_CR23","doi-asserted-by":"publisher","unstructured":"De Nunzio V, Carrieri L, Scavo MP, Lippolis T, Cofano M, Caponio GR, et al. Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors' Expression in Cultured HepaRG Cells. Int J Mol Sci. 2023;24(2). https:\/\/doi.org\/10.3390\/ijms24021739.","DOI":"10.3390\/ijms24021739"},{"key":"541_CR24","doi-asserted-by":"publisher","unstructured":"Yuan Y, He Q, Yang X, Flores JJ, Huang L, Luo X, et al. Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage. Exp Neurol. 2024;374:114703. https:\/\/doi.org\/10.1016\/j.expneurol.2024.114703.","DOI":"10.1016\/j.expneurol.2024.114703"},{"key":"541_CR25","doi-asserted-by":"publisher","DOI":"10.2174\/0118715303401342250514102731","author":"W Huang","year":"2025","unstructured":"Huang W, Meng W, Zhao J, Zhang B. Sterile Inflammation and Cell Death Pathways in Liver Ischemia-Reperfusion Injury: A Review and Perspective. Endocr Metab Immune Disord Drug Targets. 2025. https:\/\/doi.org\/10.2174\/0118715303401342250514102731.","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"issue":"3","key":"541_CR26","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1002\/hep.20620","volume":"41","author":"G Montosi","year":"2005","unstructured":"Montosi G, Corradini E, Garuti C, Barelli S, Recalcati S, Cairo G, et al. Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload. Hepatology. 2005;41(3):545\u201352. https:\/\/doi.org\/10.1002\/hep.20620.","journal-title":"Hepatology"},{"issue":"5","key":"541_CR27","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1179\/135100099101534963","volume":"4","author":"X Boisier","year":"1999","unstructured":"Boisier X, Sch\u00f6n M, Sep\u00falveda A, Basualdo A, Cornejo P, Bosco C, et al. Derangement of Kupffer cell functioning and hepatotoxicity in hyperthyroid rats subjected to acute iron overload. Redox Rep. 1999;4(5):243\u201350. https:\/\/doi.org\/10.1179\/135100099101534963.","journal-title":"Redox Rep"},{"issue":"12","key":"541_CR28","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.3324\/haematol.2017.170720","volume":"102","author":"A Pietrangelo","year":"2017","unstructured":"Pietrangelo A. Ferroportin disease: pathogenesis, diagnosis and treatment. Haematologica. 2017;102(12):1972\u201384. https:\/\/doi.org\/10.3324\/haematol.2017.170720.","journal-title":"Haematologica"},{"issue":"8","key":"541_CR29","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.3324\/haematol.2009.020123","volume":"95","author":"S Marro","year":"2010","unstructured":"Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, et al. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE\/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica. 2010;95(8):1261\u20138. https:\/\/doi.org\/10.3324\/haematol.2009.020123.","journal-title":"Haematologica"},{"key":"541_CR30","doi-asserted-by":"publisher","unstructured":"Xue D, Zhou C, Shi Y, Lu H, Xu R, and He X. Nuclear transcription factor Nrf2 suppresses prostate cancer cells growth and migration through upregulating ferroportin. Oncotarget. 2016;7(48):78804\u201378812. https:\/\/doi.org\/10.18632\/oncotarget.12860.","DOI":"10.18632\/oncotarget.12860"},{"issue":"4","key":"541_CR31","doi-asserted-by":"publisher","first-page":"932","DOI":"10.14218\/jcth.2022.00420","volume":"11","author":"K Pinyopornpanish","year":"2023","unstructured":"Pinyopornpanish K, Tantiworawit A, Leerapun A, Soontornpun A, Thongsawat S. Secondary iron overload and the liver: a comprehensive review. J Clin Transl Hepatol. 2023;11(4):932\u201341. https:\/\/doi.org\/10.14218\/jcth.2022.00420.","journal-title":"J Clin Transl Hepatol"},{"issue":"4","key":"541_CR32","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s00018-022-04239-9","volume":"79","author":"LX Li","year":"2022","unstructured":"Li LX, Guo FF, Liu H, Zeng T. Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets. Cell Mol Life Sci. 2022;79(4):201. https:\/\/doi.org\/10.1007\/s00018-022-04239-9.","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"541_CR33","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1084\/jem.20190257","volume":"216","author":"P Molina-S\u00e1nchez","year":"2019","unstructured":"Molina-S\u00e1nchez P, Lujambio A. Iron overload and liver cancer. J Exp Med. 2019;216(4):723\u20134. https:\/\/doi.org\/10.1084\/jem.20190257.","journal-title":"J Exp Med"},{"key":"541_CR34","doi-asserted-by":"publisher","unstructured":"Liang M, Chen L, He Q, Mi X, Qu L, Xie J, et al. Intraperitoneal injection of iron dextran induces peripheral iron overload and mild neurodegeneration in the nigrostriatal system in C57BL\/6 mice. Life Sci. 2023;320:121508. https:\/\/doi.org\/10.1016\/j.lfs.2023.121508.","DOI":"10.1016\/j.lfs.2023.121508"},{"issue":"11","key":"541_CR35","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1038\/s41401-019-0213-0","volume":"40","author":"ZB Huang","year":"2019","unstructured":"Huang ZB, Zheng YX, Li N, Cai SL, Huang Y, Wang J, et al. Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice. Acta Pharmacol Sin. 2019;40(11):1404\u201311. https:\/\/doi.org\/10.1038\/s41401-019-0213-0.","journal-title":"Acta Pharmacol Sin"},{"issue":"13","key":"541_CR36","doi-asserted-by":"publisher","first-page":"3217","DOI":"10.1016\/j.cgh.2023.07.031","volume":"21","author":"M Camilleri","year":"2023","unstructured":"Camilleri M, Zheng T. Cannabinoids and the gastrointestinal tract. Clin Gastroenterol Hepatol. 2023;21(13):3217\u201329. https:\/\/doi.org\/10.1016\/j.cgh.2023.07.031.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"2","key":"541_CR37","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/sj.bjp.0707531","volume":"153","author":"J Guindon","year":"2008","unstructured":"Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153(2):319\u201334. https:\/\/doi.org\/10.1038\/sj.bjp.0707531.","journal-title":"Br J Pharmacol"},{"key":"541_CR38","doi-asserted-by":"publisher","unstructured":"Cheng WT, Pei SY, Wu J, Wang YJ, Yang YW, Xiao MF, et al. Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism. Acta Pharmacol Sin. 2025. https:\/\/doi.org\/10.1038\/s41401-025-01495-w.","DOI":"10.1038\/s41401-025-01495-w"},{"key":"541_CR39","doi-asserted-by":"publisher","unstructured":"Bazwinsky-Wutschke I, Zipprich A, Dehghani F. Endocannabinoid system in hepatic glucose metabolism, fatty liver disease, and cirrhosis. Int J Mol Sci. 2019. https:\/\/doi.org\/10.3390\/ijms20102516.","DOI":"10.3390\/ijms20102516"},{"key":"541_CR40","doi-asserted-by":"publisher","unstructured":"Abate G, Uberti D, Tambaro S. Potential and limits of cannabinoids in Alzheimer\u2019s disease therapy. Biology (Basel). 2021. https:\/\/doi.org\/10.3390\/biology10060542.","DOI":"10.3390\/biology10060542"},{"key":"541_CR41","doi-asserted-by":"publisher","unstructured":"Bietar B, Tanner S, Lehmann C. Neuroprotection and beyond: the central role of CB1 and CB2 receptors in stroke recovery. Int J Mol Sci. 2023. https:\/\/doi.org\/10.3390\/ijms242316728.","DOI":"10.3390\/ijms242316728"},{"key":"541_CR42","doi-asserted-by":"publisher","unstructured":"Wu A, Feng B, Yu J, Yan L, Che L, Zhuo Y, et al. Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis. Redox Biol. 2021;46:102131. https:\/\/doi.org\/10.1016\/j.redox.2021.102131.","DOI":"10.1016\/j.redox.2021.102131"},{"key":"541_CR43","doi-asserted-by":"publisher","unstructured":"Garcia-Casal MN, Pasricha SR, Martinez RX, Lopez-Perez L, and Pe\u00f1a-Rosas JP. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database Syst Rev. 2021;5(5):Cd011817. https:\/\/doi.org\/10.1002\/14651858.CD011817.pub2.","DOI":"10.1002\/14651858.CD011817.pub2"},{"key":"541_CR44","doi-asserted-by":"publisher","unstructured":"Gopireddy RR, Bhattacharya D, Sen S, Schwartz MA, Friedman SL, Yu RC, et al. Cannabinoid Receptor 2 Activating Antibodies: A Promising Therapeutic Strategy for Macrophage-Driven Fibro-Inflammatory Diseases. bioRxiv. 2025. https:\/\/doi.org\/10.1101\/2025.07.11.664477","DOI":"10.1101\/2025.07.11.664477"},{"issue":"4","key":"541_CR45","doi-asserted-by":"publisher","first-page":"211","DOI":"10.5114\/ceh.2024.145358","volume":"10","author":"A Parfieniuk-Kowerda","year":"2024","unstructured":"Parfieniuk-Kowerda A, Martonik D, Andrzejuk A, Tarasik A, Flisiak R. Cannabinoids and the endocannabinoid system in liver diseases. Clin Exp Hepatol. 2024;10(4):211\u20137. https:\/\/doi.org\/10.5114\/ceh.2024.145358.","journal-title":"Clin Exp Hepatol"},{"issue":"6","key":"541_CR46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0253475","volume":"16","author":"E Charlebois","year":"2021","unstructured":"Charlebois E, Pantopoulos K. Iron overload inhibits BMP\/SMAD and IL-6\/STAT3 signaling to hepcidin in cultured hepatocytes. PLoS ONE. 2021;16(6):e0253475. https:\/\/doi.org\/10.1371\/journal.pone.0253475.","journal-title":"PLoS ONE"},{"issue":"4","key":"541_CR47","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.plipres.2013.05.004","volume":"52","author":"I Galve-Roperh","year":"2013","unstructured":"Galve-Roperh I, Chiurchi\u00f9 V, D\u00edaz-Alonso J, Bari M, Guzm\u00e1n M, Maccarrone M. Cannabinoid receptor signaling in progenitor\/stem cell proliferation and differentiation. Prog Lipid Res. 2013;52(4):633\u201350. https:\/\/doi.org\/10.1016\/j.plipres.2013.05.004.","journal-title":"Prog Lipid Res"},{"key":"541_CR48","doi-asserted-by":"publisher","unstructured":"Sharma R, Singh S, Whiting ZM, Molitor M, Vernall AJ, Grimsey NL. Novel cannabinoid receptor 2 (CB2) low lipophilicity agonists produce distinct cAMP and arrestin signalling kinetics without bias. Int J Mol Sci. 2023. https:\/\/doi.org\/10.3390\/ijms24076406.","DOI":"10.3390\/ijms24076406"},{"key":"541_CR49","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1477122","volume":"15","author":"P Luo","year":"2024","unstructured":"Luo P, Chen T, Zheng L, Zou J, Zou J, Li W, et al. Calcium sensing receptor regulate claudin-14 via PKA-STAT3 pathway in rat model of nephrolithiasis. Front Pharmacol. 2024;15:1477122. https:\/\/doi.org\/10.3389\/fphar.2024.1477122.","journal-title":"Front Pharmacol"},{"issue":"26","key":"541_CR50","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1038\/s41388-018-0218-z","volume":"37","author":"AR \u00d6ze\u015f","year":"2018","unstructured":"\u00d6ze\u015f AR, Pulliam N, Ertosun MG, Y\u0131lmaz \u00d6, Tang J, \u00c7opuro\u011flu E, et al. Protein kinase A-mediated phosphorylation regulates STAT3 activation and oncogenic EZH2 activity. Oncogene. 2018;37(26):3589\u2013600. https:\/\/doi.org\/10.1038\/s41388-018-0218-z.","journal-title":"Oncogene"},{"issue":"6","key":"541_CR51","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1016\/j.jhep.2017.02.026","volume":"66","author":"F Tacke","year":"2017","unstructured":"Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66(6):1300\u201312. https:\/\/doi.org\/10.1016\/j.jhep.2017.02.026.","journal-title":"J Hepatol"},{"key":"541_CR52","doi-asserted-by":"publisher","unstructured":"Yu L, Wang M, Zhou Y, Qi J, Zheng Q, and Song Z. NLRP3 Mediates NOXs-Induced Iron Overload and Inflammation but Not Oxidative Damage in Colons of DSS-Treated Mice. J Inflamm Res. 2025;18:4695\u20134708. https:\/\/doi.org\/10.2147\/jir.S509168","DOI":"10.2147\/jir.S509168"},{"key":"541_CR53","doi-asserted-by":"publisher","unstructured":"Qin R, Cao J, Li J, Qiu D, Lin H, Wang Y, et al. Targeting iron overload and macrophage polarization to treat diabetic periodontitis: Mechanisms and therapeutic strategies. Life Sci. 2025;377:123805. https:\/\/doi.org\/10.1016\/j.lfs.2025.123805.","DOI":"10.1016\/j.lfs.2025.123805"},{"issue":"4","key":"541_CR54","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.immuni.2019.09.002","volume":"51","author":"M Sakai","year":"2019","unstructured":"Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, et al. Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Immunity. 2019;51(4):655-670.e8. https:\/\/doi.org\/10.1016\/j.immuni.2019.09.002.","journal-title":"Immunity"},{"issue":"4","key":"541_CR55","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1002\/hep.24524","volume":"54","author":"A Louvet","year":"2011","unstructured":"Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54(4):1217\u201326. https:\/\/doi.org\/10.1002\/hep.24524.","journal-title":"Hepatology"},{"issue":"10","key":"541_CR56","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1002\/tox.23615","volume":"37","author":"S Guan","year":"2022","unstructured":"Guan S, Zhang R, Zhao Y, Meng Z, Lu J. 1,3-Dichloro-2-propanol induced ferroptosis through Nrf2\/ARE signaling pathway in hepatocytes. Environ Toxicol. 2022;37(10):2515\u201328. https:\/\/doi.org\/10.1002\/tox.23615.","journal-title":"Environ Toxicol"},{"issue":"2","key":"541_CR57","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s12192-022-01257-1","volume":"27","author":"H Tian","year":"2021","unstructured":"Tian H, Xiong Y, Zhang Y, Leng Y, Tao J, Li L, et al. Activation of NRF2\/FPN1 pathway attenuates myocardial ischemia-reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis. Cell Stress Chaperones. 2021;27(2):149\u201364. https:\/\/doi.org\/10.1007\/s12192-022-01257-1.","journal-title":"Cell Stress Chaperones"},{"key":"541_CR58","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.ebiom.2019.03.040","volume":"42","author":"Z Ma","year":"2019","unstructured":"Ma Z, Gao F, Larsen B, Gao M, Luo Z, Chen D, et al. Mechanisms of cannabinoid CB(2) receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area. EBioMedicine. 2019;42:225\u201337. https:\/\/doi.org\/10.1016\/j.ebiom.2019.03.040.","journal-title":"EBioMedicine"},{"key":"541_CR59","doi-asserted-by":"publisher","unstructured":"Mendoza R, Banerjee I, Reghupaty SC, Yetirajam R, Manna D, and Sarkar D. Isolation and Culture of Mouse Hepatocytes and Kupffer Cells (KCs). Methods Mol Biol. 2022;2455:73\u201384. https:\/\/doi.org\/10.1007\/978-1-0716-2128-8_7.","DOI":"10.1007\/978-1-0716-2128-8_7"},{"key":"541_CR60","doi-asserted-by":"publisher","unstructured":"Dena\u00ebs T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, et al. The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway. Sci Rep. 2016;6:28806. https:\/\/doi.org\/10.1038\/srep28806.","DOI":"10.1038\/srep28806"},{"issue":"5","key":"541_CR61","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1007\/s11033-023-08395-4","volume":"50","author":"M Wang","year":"2023","unstructured":"Wang M, Liu M, Ma Z. Cannabinoid type 2 receptor activation inhibits MPP(+)-induced M1 differentiation of microglia through activating PI3K\/Akt\/Nrf2 signal pathway. Mol Biol Rep. 2023;50(5):4423\u201333. https:\/\/doi.org\/10.1007\/s11033-023-08395-4.","journal-title":"Mol Biol Rep"},{"issue":"18","key":"541_CR62","doi-asserted-by":"publisher","first-page":"8366","DOI":"10.1039\/d1fo01360b","volume":"12","author":"H Deng","year":"2021","unstructured":"Deng H, Ma Z. Protective effects of berberine against MPTP-induced dopaminergic neuron injury through promoting autophagy in mice. Food Funct. 2021;12(18):8366\u201375. https:\/\/doi.org\/10.1039\/d1fo01360b.","journal-title":"Food Funct"}],"container-title":["Molecular Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00541-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43556-026-00541-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00541-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:03:32Z","timestamp":1786370612000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s43556-026-00541-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["541"],"URL":"https:\/\/doi.org\/10.1186\/s43556-026-00541-1","relation":{},"ISSN":["2662-8651"],"issn-type":[{"value":"2662-8651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"assertion":[{"value":"7 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study has no clinical trials. All animal studies were conducted in accordance with the Regulations on the Management of Laboratory Animals issued by the Animal Committee of Qingdao University (Ethical number: QDU-AEC-2024452).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"135"}}