{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:07:45Z","timestamp":1790690865889,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fanhuncao (\n                    <jats:italic>Jacobaea cannabifolia<\/jats:italic>\n                    and\n                    <jats:italic>J. litvinovii<\/jats:italic>\n                    ) is a traditional Chinese herb with reported antitumor potential. Retrorsine, a pyrrolizidine alkaloid from Fanhuncao, requires CYP3A4\u2011mediated metabolic activation, but its dual outcomes (anti\u2011liver cancer efficacy vs. organ\u2011specific toxicity) remain unclear. To elucidate how CYP3A4\u2010dependent activation of retrorsine drives both anti\u2010liver cancer activity and organ\u2010specific toxicity, and to identify differential cell death pathways in target organs. UPLC\u2010HRMS profiled pyrrolizidine alkaloids in Fanhuncao. Cytotoxicity screening, molecular docking, and molecular dynamics identified retrorsine as the lead compound. Network pharmacology\/toxicology predicted targets of dehydro\u2010retrorsine. In vitro assays and Western blotting were performed on hepatoma cells.\n                    <jats:italic>In vivo<\/jats:italic>\n                    efficacy and toxicity were evaluated in H22 tumor\u2010bearing mice. Retrorsine achieved significant tumor growth inhibition at high dose. Mechanistically, it simultaneously inhibited EGFR\/PI3K\/AKT\/mTOR and NF\u2010\u03baB pathways while activating intrinsic mitochondrial apoptosis (altered Bax\/Bcl\u20102, cytochrome c release, Caspase\u20109\/3 activation). Retrorsine upregulated CYP3A4 in tumor cells, suggesting a potential self\u2011amplifying metabolic loop that requires further validation. However, this efficacy was accompanied by dose\u2010dependent hepatorenal toxicity with organ\u2010specific mechanisms: liver injury via oxidative stress and mitochondrial apoptosis; kidney injury via Caspase\u20103\/GSDME\u2010dependent pyroptosis. Retrorsine is a potent multi\u2010target anti\u2010liver cancer natural product, but its therapeutic window is narrowed by inseparable organ\u2010specific toxicities (hepatic apoptosis vs. renal pyroptosis) arising from CYP3A4\u2010dependent metabolic activation. Future decoupling strategies should focus on targeted delivery, structural modification, or combination therapies.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70326","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:30:55Z","timestamp":1788787855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Activation\u2010Dependent Anti\u2010Liver Cancer Activity and Organ\u2010Specific Toxicity of Retrorsine From Fanhuncao (\n                    <i>Jacobaea cannabifolia<\/i>\n                    and\n                    <i>J. litvinovii<\/i>\n                    )"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0470-0105","authenticated-orcid":false,"given":"Zhijie","family":"He","sequence":"first","affiliation":[{"name":"School of Pharmacy Changchun University of Chinese Medicine Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Pharmacy Changchun University of Chinese Medicine Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lunrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials Jilin Agricultural University Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine Changchun University of Chinese Medicine Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yedeli","family":"Yerjiang","sequence":"additional","affiliation":[{"name":"School of Acupuncture and Tuina Changchun University of Chinese Medicine Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Bi","sequence":"additional","affiliation":[{"name":"School of Pharmacy Changchun University of Chinese Medicine Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingshan","family":"Bao","sequence":"additional","affiliation":[{"name":"College of Chinese Medicinal Materials Jilin Agricultural University Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00264-x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.08.021"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0186-y"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00825-3"},{"key":"e_1_2_9_6_1","unstructured":"Committee on Biodiversity Chinese Academy of Sciences \u201cCatalogue of Life China \u201d Online Database accessed on April 5 2026 https:\/\/wwwsp2000.org.cn\/."},{"key":"e_1_2_9_7_1","unstructured":"World Flora Online \u201cWorld Flora Online \u201d Online Database accessed April 5 2026 http:\/\/wwwworldfloraonline.org."},{"key":"e_1_2_9_8_1","first-page":"149","volume-title":"Jilin Provincial Standards for Chinese Medicinal Materials","author":"Shen L.","year":"2019"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.120812"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2025.106965"},{"key":"e_1_2_9_11_1","first-page":"98","article-title":"Bacteriostatic Test and Acute and Subacute Toxicity Test of \u2018Fanhuncao\u2019","volume":"1","author":"Ren J. X.","year":"1979","journal-title":"Jilin Journal of Traditional Chinese Medicine"},{"issue":"6","key":"e_1_2_9_12_1","first-page":"436","article-title":"Advances in Pharmaceutical Research of Senecio cannabifolius Herba","volume":"28","author":"Wu Y. F.","year":"2009","journal-title":"Shandong Journal of Traditional Chinese Medicine"},{"issue":"3","key":"e_1_2_9_13_1","first-page":"266","article-title":"Research Progress on Pharmacological Effects of Main Components and Extracts of Senecio cannabifolius Herba","volume":"32","author":"Sun J. D.","year":"2016","journal-title":"Pharmaceutical Journal of Chinese People's Liberation Army"},{"issue":"4","key":"e_1_2_9_14_1","first-page":"670","article-title":"Discussion on the Quality Evaluation Standard of Senecio cannabifolii Herba","volume":"36","author":"Jiang R. Z.","year":"2020","journal-title":"Journal of Changchun University of Traditional Chinese Medicine"},{"issue":"11","key":"e_1_2_9_15_1","first-page":"1039","article-title":"Risk Assessment and Determination of Hepatotoxic Pyrrolizidine Alkaloids in Senecio cannabifolii Herba","volume":"18","author":"Zan K.","year":"2021","journal-title":"Chin. J. Pharmacovigilance"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.8b00096"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.livres.2019.11.004"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.2020.34.s1.08851"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13120849"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins14090633"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242316972"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.27280"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-021-03204-y"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.104"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2023-1739"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106553"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-023-00438-9"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01207-z"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2024.101009"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx500403t"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19061668"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc883"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00689-6"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01284-8"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02895-z"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-023-03482-8"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-024-03698-2"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2023.117390"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990470"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01607-9"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medidd.2025.100220"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2019.111107"},{"key":"e_1_2_9_43_1","article-title":"Regulatory Role of Oxidative Stress in Retrorsine\u2010Induced Apoptosis and Autophagy in Primary Rat Hepatocytes","volume":"278","author":"Zhu Y.","year":"2024","journal-title":"Ecotoxicology and Environmental Safety"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2026.108998"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-62071-8"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4202"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910040106"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.02.022"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2016.1225856"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-021-03060-w"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2284"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16723"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9253-1"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2015.01.053"},{"issue":"2","key":"e_1_2_9_55_1","first-page":"181","article-title":"Microsomal Formation of a Pyrrolic Alcohol Glutathione Conjugate of Clivorine. Firm Evidence for the Formation of a Pyrrolic Metabolite of an Otonecine\u2010Type Pyrrolizidine Alkaloid","volume":"26","author":"Lin G.","year":"1998","journal-title":"Drug Metabolism and Disposition: The Biological Fate of Chemicals"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1080\/10590501.2015.1096882"},{"key":"e_1_2_9_57_1","unstructured":"X. J.Yang \u201cMechanistic Studies of Hepatotoxicities Induced by Retrorsine and Monocrotaline\u201d (Doctoral diss. Shenyang Pharmaceutical University 2018)."}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70326","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ardp.70326","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70326","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:32:20Z","timestamp":1790688740000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.70326"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":56,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/ardp.70326"],"URL":"https:\/\/doi.org\/10.1002\/ardp.70326","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"value":"0365-6233","type":"print"},{"value":"1521-4184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70326"}}