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Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Two mouse models, iron supplement\u2010induced hepatic ferroptosis and hepatic ischaemia\/reperfusion (I\/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)\/pharmacodynamics (PD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I\/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR\u2013signal transducer and activator of transcription 3 (STAT3)\u2013haem oxygenase 1\/COX\u20102 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I\/R injury. In mice pre\u2010treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16208","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T07:49:31Z","timestamp":1691135371000},"page":"125-141","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["AhR\u2013STAT3\u2013HO\u20101\/COX\u20102 signalling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mouse liver"],"prefix":"10.1111","volume":"181","author":[{"given":"Li","family":"Han","sequence":"first","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhui","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"Department of Chemical and Environmental Engineering University of Nottingham Ningbo China  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhitao","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes, Renji\u2010Med\u2010X Clinical Stem Cell Research Center Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6731-5803","authenticated-orcid":false,"given":"Guoyu","family":"Pan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15537"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15543"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101855"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114093"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.12.025"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.637162"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau9940"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.03.001"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02332-9"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00297"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009001"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfv206"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2017.02.006"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.14081"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015050578"},{"key":"e_1_2_12_20_1","article-title":"Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion\u2010dependent thalassaemia","volume":"8","author":"Fisher S. 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