{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:24:40Z","timestamp":1792373080354,"version":"4.4.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T00:00:00Z","timestamp":1716422400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T00:00:00Z","timestamp":1716422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2\/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2\/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2\/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.<\/jats:p>","DOI":"10.1038\/s42003-024-06243-0","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T15:02:53Z","timestamp":1716476573000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Activation of Nrf2\/HO-1 signaling pathway exacerbates cholestatic liver injury"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2692-6890","authenticated-orcid":false,"given":"Yi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8043-3440","authenticated-orcid":false,"given":"Xiaolong","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongyang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siting","family":"Xian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songjie","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Klaunig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0698-1597","authenticated-orcid":false,"given":"Yuanfu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-7462","authenticated-orcid":false,"given":"Shaoyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,23]]},"reference":[{"key":"6243_CR1","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.jhep.2022.05.044","volume":"77","author":"I Labiano","year":"2022","unstructured":"Labiano, I. et al. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. J. Hepatol. 77, 991\u20131004 (2022).","journal-title":"J. Hepatol."},{"key":"6243_CR2","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/hep.31494","volume":"73","author":"M Frissen","year":"2021","unstructured":"Frissen, M. et al. Bidirectional role of NLRP3 during acute and chronic cholestatic liver injury. Hepatology 73, 1836\u20131854 (2021).","journal-title":"Hepatology"},{"key":"6243_CR3","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1007\/s10529-017-2396-0","volume":"39","author":"V Hooda","year":"2017","unstructured":"Hooda, V., Gahlaut, A., Gothwal, A. & Hooda, V. Bilirubin enzyme biosensor: potentiality and recent advances towards clinical bioanalysis. Biotechnol. Lett. 39, 1453\u20131462 (2017).","journal-title":"Biotechnol. Lett."},{"key":"6243_CR4","doi-asserted-by":"publisher","first-page":"5171","DOI":"10.1073\/pnas.0813132106","volume":"106","author":"TW Sedlak","year":"2009","unstructured":"Sedlak, T. W. et al. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc. Natl Acad. Sci. USA 106, 5171\u20135176 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"6243_CR5","doi-asserted-by":"publisher","first-page":"29251","DOI":"10.1074\/jbc.M109.037119","volume":"284","author":"GJ Maghzal","year":"2009","unstructured":"Maghzal, G. J., Leck, M. C., Collinson, E., Li, C. & Stocker, R. Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase. J. Biol. Chem. 284, 29251\u201329259 (2009).","journal-title":"J. Biol. Chem."},{"key":"6243_CR6","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.siny.2009.10.005","volume":"15","author":"AF McDonagh","year":"2010","unstructured":"McDonagh, A. F. Controversies in bilirubin biochemistry and their clinical relevance. Semin. Fetal Neonatal. Med. 15, 141\u2013147 (2010).","journal-title":"Semin. Fetal Neonatal. Med."},{"key":"6243_CR7","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1056\/NEJMra1308124","volume":"369","author":"JF Watchko","year":"2013","unstructured":"Watchko, J. F. & Tiribelli, C. Bilirubin-induced neurologic damage-mechanisms and management approaches. N. Engl. J. Med. 369, 2021\u20132030 (2013).","journal-title":"N. Engl. J. Med."},{"key":"6243_CR8","doi-asserted-by":"publisher","first-page":"118032","DOI":"10.1016\/j.lfs.2020.118032","volume":"257","author":"P Nov\u00e1k","year":"2020","unstructured":"Nov\u00e1k, P., Jackson, A. O., Zhao, G. J. & Yin, K. Bilirubin in metabolic syndrome and associated inflammatory diseases: New perspectives. Life Sci. 257, 118032 (2020).","journal-title":"Life Sci"},{"key":"6243_CR9","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.7150\/ijbs.69116","volume":"18","author":"Z Gao","year":"2022","unstructured":"Gao, Z. et al. Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2. Int. J. Biol. Sci. 18, 2146\u20132162 (2022).","journal-title":"Int. J. Biol. Sci"},{"key":"6243_CR10","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez, M. J. et al. Maresin-1 prevents liver fibrosis by targeting Nrf2 and NF-\u03baB, reducing oxidative stress and inflammation. Cells 10, 3406 (2021).","DOI":"10.3390\/cells10123406"},{"key":"6243_CR11","doi-asserted-by":"publisher","first-page":"G925","DOI":"10.1152\/ajpgi.00263.2011","volume":"302","author":"J Weerachayaphorn","year":"2012","unstructured":"Weerachayaphorn, J. et al. Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine. Am J. Physiol. Gastrointest. Liver Physiol. 302, G925\u2013G936 (2012).","journal-title":"Am J. Physiol. Gastrointest. Liver Physiol."},{"key":"6243_CR12","doi-asserted-by":"publisher","first-page":"e0269383","DOI":"10.1371\/journal.pone.0269383","volume":"17","author":"GY Wang","year":"2022","unstructured":"Wang, G. Y. et al. Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model. PLoS ONE 17, e0269383 (2022).","journal-title":"PLoS ONE"},{"key":"6243_CR13","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1177\/0960327120905962","volume":"39","author":"MJ Khodayar","year":"2020","unstructured":"Khodayar, M. J., Kalantari, H., Khorsandi, L., Rashno, M. & Zeidooni, L. Upregulation of Nrf2-related cytoprotective genes expression by acetaminophen-induced acute hepatotoxicity in mice and the protective role of betaine. Hum. Exp. Toxicol. 39, 948\u2013959 (2020).","journal-title":"Hum. Exp. Toxicol."},{"key":"6243_CR14","doi-asserted-by":"publisher","first-page":"976","DOI":"10.3390\/antiox10060976","volume":"10","author":"C Dai","year":"2021","unstructured":"Dai, C. et al. Inhibition of oxidative stress and ALOX12 and NF-\u03baB pathways contribute to the protective effect of baicalein on carbon tetrachloride-induced acute liver injury. Antioxidants 10, 976 (2021).","journal-title":"Antioxidants"},{"key":"6243_CR15","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.taap.2013.08.003","volume":"272","author":"J Liu","year":"2013","unstructured":"Liu, J. et al. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice. Toxicol. Appl. Pharmacol. 272, 816\u2013824 (2013).","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"6243_CR16","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1073\/pnas.96.5.2445","volume":"96","author":"S Dor\u00e9","year":"1999","unstructured":"Dor\u00e9, S. et al. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl Acad. Sci. USA 96, 2445\u20132450 (1999).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"6243_CR17","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.cellsig.2013.11.029","volume":"26","author":"M Qaisiya","year":"2014","unstructured":"Qaisiya, M., Coda Zabetta, C. D., Bellarosa, C. & Tiribelli, C. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal 26, 512\u2013520 (2014).","journal-title":"Cell Signal"},{"key":"6243_CR18","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1002\/jat.4298","volume":"42","author":"H Feng","year":"2022","unstructured":"Feng, H., Hu, Y., Zhou, S. & Lu, Y. Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice. J. Appl. Toxicol. 42, 1323\u20131336 (2022).","journal-title":"J. Appl. Toxicol."},{"key":"6243_CR19","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.3748\/wjg.v19.i19.2921","volume":"19","author":"QM Wang","year":"2013","unstructured":"Wang, Q. M. et al. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J. Gastroenterol. 19, 2921\u20132934 (2013).","journal-title":"World J. Gastroenterol."},{"key":"6243_CR20","doi-asserted-by":"publisher","first-page":"3478","DOI":"10.3748\/wjg.v13.i25.3478","volume":"13","author":"M Froh","year":"2007","unstructured":"Froh, M. et al. Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J. Gastroenterol. 13, 3478\u20133486 (2007).","journal-title":"World J. Gastroenterol"},{"key":"6243_CR21","doi-asserted-by":"publisher","first-page":"3406","DOI":"10.1016\/j.bcp.2021.114863","volume":"195","author":"W Yang","year":"2022","unstructured":"Yang, W. et al. Maresin 1 protects against lipopolysaccharide\/d-galactosamine-induced acute liver injury by inhibiting macrophage pyroptosis and inflammatory response. Biochem. Pharmacol. 195, 3406 (2022).","journal-title":"Biochem. Pharmacol"},{"key":"6243_CR22","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2022.02.030","volume":"182","author":"W Yang","year":"2022","unstructured":"Yang, W. et al. Immune-responsive gene 1 protects against liver injury caused by concanavalin A via the activation Nrf2\/HO-1 pathway and inhibition of ROS activation pathways. Free Radic. Biol. Med. 182, 108\u2013118 (2022).","journal-title":"Free Radic. Biol. Med"},{"key":"6243_CR23","doi-asserted-by":"publisher","first-page":"42887","DOI":"10.1021\/acsami.2c10506","volume":"14","author":"X Cai","year":"2022","unstructured":"Cai, X. et al. Astaxanthin activated the Nrf2\/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury. ACS Appl. Mater. Interfaces 14, 42887\u201342903 (2022).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"6243_CR24","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1006\/taap.1993.1049","volume":"119","author":"DC Kossor","year":"1993","unstructured":"Kossor, D. C., Meunier, P. C., Handler, J. A., Sozio, R. S. & Goldstein, R. S. Temporal relationship of changes in hepatobiliary function and morphology in rats following alpha-naphthylisothiocyanate (ANIT) administration. Toxicol. Appl. Pharmacol. 119, 108\u2013114 (1993).","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"6243_CR25","doi-asserted-by":"publisher","first-page":"E244","DOI":"10.1152\/ajpendo.00396.2016","volume":"312","author":"TD Hinds Jr.","year":"2017","unstructured":"Hinds, T. D. Jr. et al. Mice with hyperbilirubinemia due to Gilbert\u2019s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPAR\u03b1. Am. J. Physiol. Endocrinol. Metab. 312, E244\u2013e252 (2017).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"6243_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/srep09886","volume":"5","author":"J Liu","year":"2015","unstructured":"Liu, J. et al. Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPAR\u03b3 levels. Sci. Rep. 5, 9886 (2015).","journal-title":"Sci. Rep."},{"key":"6243_CR27","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1002\/hep.21879","volume":"46","author":"AK Peyer","year":"2007","unstructured":"Peyer, A. K. et al. Regulation of human liver delta-aminolevulinic acid synthase by bile acids. Hepatology 46, 1960\u20131970 (2007).","journal-title":"Hepatology"},{"key":"6243_CR28","doi-asserted-by":"publisher","first-page":"109073","DOI":"10.1016\/j.biopha.2019.109073","volume":"117","author":"S Li","year":"2019","unstructured":"Li, S. et al. Induction of Nrf2 pathway by Dendrobium nobile Lindl. alkaloids protects against carbon tetrachloride induced acute liver injury. Biomed. Pharmacother. 117, 109073 (2019).","journal-title":"Biomed. Pharmacother."},{"key":"6243_CR29","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.jhep.2020.04.025","volume":"73","author":"S Lefere","year":"2020","unstructured":"Lefere, S. et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 73, 757\u2013770 (2020).","journal-title":"J. Hepatol."},{"key":"6243_CR30","first-page":"380","volume":"254","author":"T Kamisako","year":"1990","unstructured":"Kamisako, T., Adachi, Y. & Yamamoto, T. Effect of UDP-glucuronic acid depletion by salicylamide on biliary bilirubin excretion in the rat. J. Pharmacol. Exp. Ther. 254, 380\u2013382 (1990).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"6243_CR31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0168-8278(00)80411-0","volume":"32","author":"GA Kullak-Ublick","year":"2000","unstructured":"Kullak-Ublick, G. A., Beuers, U. & Paumgartner, G. Hepatobiliary transport. J. Hepatol. 32, 3\u201318 (2000).","journal-title":"J. Hepatol."},{"key":"6243_CR32","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.jhep.2005.02.030","volume":"43","author":"HL Chen","year":"2005","unstructured":"Chen, H. L. et al. Developmental expression of canalicular transporter genes in human liver. J. Hepatol. 43, 472\u2013477 (2005).","journal-title":"J. Hepatol."},{"key":"6243_CR33","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1136\/gutjnl-2022-326987","volume":"72","author":"S Wang","year":"2023","unstructured":"Wang, S. et al. FOXA2 prevents hyperbilirubinaemia in acute liver failure by maintaining apical MRP2 expression. Gut 72, 549\u2013559 (2023).","journal-title":"Gut"},{"key":"6243_CR34","doi-asserted-by":"publisher","first-page":"6403","DOI":"10.1016\/S0021-9258(18)63479-9","volume":"244","author":"MG Mustafa","year":"1969","unstructured":"Mustafa, M. G., Cowger, M. L. & King, T. E. Effects of bilirubin on mitochondrial reactions. J. Biol. Chem. 244, 6403\u20136414 (1969).","journal-title":"J. Biol. Chem."},{"key":"6243_CR35","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12929-018-0475-8","volume":"25","author":"HL Chen","year":"2018","unstructured":"Chen, H. L. et al. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J. Biomed. Sci. 25, 75 (2018).","journal-title":"J. Biomed. Sci."},{"key":"6243_CR36","doi-asserted-by":"publisher","first-page":"3067","DOI":"10.1021\/mp4001348","volume":"10","author":"JH Chang","year":"2013","unstructured":"Chang, J. H., Plise, E., Cheong, J., Ho, Q. & Lin, M. Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Mol. Pharm. 10, 3067\u20133075 (2013).","journal-title":"Mol. Pharm."},{"key":"6243_CR37","doi-asserted-by":"crossref","unstructured":"KimK, M. & Ki, S. H. Chapter 28 - nrf2: A Key Regulator of Redox Signaling in Liver Diseases (ed. Muriel, P.) (Liver Pathophysiology, Academic Press, 2017).","DOI":"10.1016\/B978-0-12-804274-8.00028-X"},{"key":"6243_CR38","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.freeradbiomed.2019.07.036","volume":"143","author":"CT Shearn","year":"2019","unstructured":"Shearn, C. T. et al. Cholestatic liver disease results increased production of reactive aldehydes and an atypical periportal hepatic antioxidant response. Free Radic. Biol. Med. 143, 101\u2013114 (2019).","journal-title":"Free Radic. Biol. Med."},{"key":"6243_CR39","doi-asserted-by":"publisher","first-page":"105422","DOI":"10.1016\/j.envint.2019.105422","volume":"136","author":"V Vilas-Boas","year":"2020","unstructured":"Vilas-Boas, V., Gijbels, E., Jonckheer, J., De Waele, E. & Vinken, M. Cholestatic liver injury induced by food additives, dietary supplements and parenteral nutrition. Environ. Int. 136, 105422 (2020).","journal-title":"Environ. Int."},{"key":"6243_CR40","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1093\/toxsci\/kfy295","volume":"168","author":"X Wang","year":"2019","unstructured":"Wang, X. et al. Paradoxical effects of emodin on ANIT-induced intrahepatic cholestasis and herb-induced hepatotoxicity in mice. Toxicol. Sci. 168, 264\u2013278 (2019).","journal-title":"Toxicol. Sci."},{"key":"6243_CR41","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/j.gastro.2005.05.009","volume":"129","author":"HU Marschall","year":"2005","unstructured":"Marschall, H. U. et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129, 476\u2013485 (2005).","journal-title":"Gastroenterology"},{"key":"6243_CR42","doi-asserted-by":"publisher","first-page":"737","DOI":"10.21037\/atm-20-5110","volume":"9","author":"SY Cai","year":"2021","unstructured":"Cai, S. Y. & Boyer, J. L. The role of bile acids in cholestatic liver injury. Ann. Transl. Med. 9, 737 (2021).","journal-title":"Ann. Transl. Med."},{"key":"6243_CR43","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.canlet.2017.12.025","volume":"416","author":"LC Chang","year":"2018","unstructured":"Chang, L. C. et al. Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Lett. 416, 124\u2013137 (2018).","journal-title":"Cancer Lett."},{"key":"6243_CR44","doi-asserted-by":"publisher","first-page":"101789","DOI":"10.1016\/j.redox.2020.101789","volume":"38","author":"C Fern\u00e1ndez-Mend\u00edvil","year":"2021","unstructured":"Fern\u00e1ndez-Mend\u00edvil, C. et al. Protective role of microglial HO-1 blockade in aging: implication of iron metabolism. Redox Biol. 38, 101789 (2021).","journal-title":"Redox Biol"},{"key":"6243_CR45","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.7150\/ijbs.59404","volume":"17","author":"R Wei","year":"2021","unstructured":"Wei, R. et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int. J. Biol. Sci. 17, 2703\u20132717 (2021).","journal-title":"Int. J. Biol. Sci"},{"key":"6243_CR46","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1055\/s-0030-1253228","volume":"30","author":"BL Copple","year":"2010","unstructured":"Copple, B. L., Jaeschke, H. & Klaassen, C. D. Oxidative stress and the pathogenesis of cholestasis. Semin. Liver Dis. 30, 195\u2013204 (2010).","journal-title":"Semin. Liver Dis."},{"key":"6243_CR47","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.bbrc.2009.08.156","volume":"389","author":"K Okada","year":"2009","unstructured":"Okada, K. et al. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems. Biochem. Biophys. Res. Commun. 389, 431\u2013436 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"6243_CR48","doi-asserted-by":"publisher","first-page":"174447","DOI":"10.1016\/j.ejphar.2021.174447","volume":"910","author":"L He","year":"2021","unstructured":"He, L., Guo, C., Peng, C. & Li, Y. Advances of natural activators for Nrf2 signaling pathway on cholestatic liver injury protection: a review. Eur. J. Pharmacol. 910, 174447 (2021).","journal-title":"Eur. J. Pharmacol."},{"key":"6243_CR49","doi-asserted-by":"publisher","first-page":"114043","DOI":"10.1016\/j.biopha.2022.114043","volume":"157","author":"X Fu","year":"2023","unstructured":"Fu, X. et al. Dendrobium and its active ingredients: emerging role in liver protection. Biomed. Pharmacother. 157, 114043 (2023).","journal-title":"Biomed. Pharmacother."},{"key":"6243_CR50","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.bcp.2018.01.026","volume":"150","author":"L Shi","year":"2018","unstructured":"Shi, L. et al. Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: the involvement of ERK1\/2 and PKC. Biochem. Pharmacol. 150, 9\u201323 (2018).","journal-title":"Biochem. Pharmacol"},{"key":"6243_CR51","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1002\/jat.4456","volume":"43","author":"J Huang","year":"2023","unstructured":"Huang, J. et al. AMP-activated protein kinase-farnesoid X receptor pathway contributes to oleanolic acid-induced liver injury. J. Appl. Toxicol. 43, 1201\u20131213 (2023).","journal-title":"J. Appl. Toxicol."},{"key":"6243_CR52","doi-asserted-by":"publisher","first-page":"116509","DOI":"10.1016\/j.taap.2023.116509","volume":"467","author":"S Liao","year":"2023","unstructured":"Liao, S. et al. Suppression of SIRT1\/FXR signaling pathway contributes to oleanolic acid-induced liver injury. Toxicol. Appl. Pharmacol. 467, 116509 (2023).","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"6243_CR53","doi-asserted-by":"publisher","first-page":"708645","DOI":"10.3389\/fphar.2021.708645","volume":"12","author":"X Wang","year":"2021","unstructured":"Wang, X., Wang, Z., Cao, J., Dong, Y. & Chen, Y. Melatonin alleviates acute sleep deprivation-induced memory loss in mice by suppressing hippocampal ferroptosis. Front. Pharmacol. 12, 708645 (2021).","journal-title":"Front. Pharmacol."},{"key":"6243_CR54","doi-asserted-by":"publisher","first-page":"113432","DOI":"10.1016\/j.jep.2020.113432","volume":"266","author":"W Hua","year":"2021","unstructured":"Hua, W. et al. Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice. J. Ethnopharmacol. 266, 113432 (2021).","journal-title":"J. Ethnopharmacol."},{"key":"6243_CR55","doi-asserted-by":"publisher","first-page":"110351","DOI":"10.1016\/j.biopha.2020.110351","volume":"129","author":"J Zhou","year":"2020","unstructured":"Zhou, J. et al. Dendrobium nobile Lindl. alkaloids-mediated protection against CCl4-induced liver mitochondrial oxidative damage is dependent on the activation of Nrf2 signaling pathway. Biomed. Pharmacother. 129, 110351 (2020).","journal-title":"Biomed. Pharmacother."},{"key":"6243_CR56","doi-asserted-by":"publisher","first-page":"e13523","DOI":"10.1111\/acel.13523","volume":"20","author":"YL Huang","year":"2021","unstructured":"Huang, Y. L., Shen, Z. Q., Huang, C. H., Lin, C. H. & Tsai, T. F. Cisd2 slows down liver aging and attenuates age-related metabolic dysfunction in male mice. Aging Cell 20, e13523 (2021).","journal-title":"Aging Cell"},{"key":"6243_CR57","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1136\/gut.52.12.1774","volume":"52","author":"A Granato","year":"2003","unstructured":"Granato, A. et al. Bilirubin inhibits bile acid induced apoptosis in rat hepatocytes. Gut 52, 1774\u20131778 (2003).","journal-title":"Gut"},{"key":"6243_CR58","first-page":"361","volume":"2","author":"ME Kauffman","year":"2016","unstructured":"Kauffman, M. E. et al. MitoSOX-based flow cytometry for detecting mitochondrial ROS. React. Oxyg. Species 2, 361\u2013370 (2016).","journal-title":"React. Oxyg. Species"},{"key":"6243_CR59","doi-asserted-by":"publisher","first-page":"45416","DOI":"10.1021\/acsami.9b16286","volume":"11","author":"H Fan","year":"2019","unstructured":"Fan, H. et al. Plasmon-enhanced oxidase-like activity and cellular effect of Pd-coated gold nanorods. ACS Appl. Mater. Interfaces 11, 45416\u201345426 (2019).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"6243_CR60","doi-asserted-by":"publisher","first-page":"114639","DOI":"10.1016\/j.taap.2019.114639","volume":"379","author":"R Zeng","year":"2019","unstructured":"Zeng, R. et al. Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. Toxicol. Appl. Pharmacol. 379, 114639 (2019).","journal-title":"Toxicol. Appl. Pharmacol"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-024-06243-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-024-06243-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-024-06243-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T15:12:07Z","timestamp":1716477127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-024-06243-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,23]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["6243"],"URL":"https:\/\/doi.org\/10.1038\/s42003-024-06243-0","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,23]]},"assertion":[{"value":"15 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"621"}}