{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:28:54Z","timestamp":1788845334890,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"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":["82074113"],"award-info":[{"award-number":["82074113"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb\/c and C57BL\/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis.<\/jats:p>","DOI":"10.3390\/ph18071078","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T17:27:36Z","timestamp":1753118856000},"page":"1078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to Ferroptosis"],"prefix":"10.3390","volume":"18","author":[{"given":"Jiajie","family":"Ni","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liru","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feihai","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"},{"name":"School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1007\/s11655-021-3442-2","article-title":"Landscape of Hepatobiliary Adverse Drug Reactions Related to Preparations Containing Psoraleae Fructus and Its Application in Pharmacovigilance","volume":"27","author":"Ge","year":"2021","journal-title":"Chin. J. Integr. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yang, Y., Ge, F.L., Tang, J.F., Qin, S.L., Zeng, R., Yao, M.L., Xiao, X.H., Bai, Z.F., and Tang, C.L. (2022). A review of herb-induced liver injury in mainland china. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.813073"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chang, H., Wang, C., Gong, L.L., Zhang, Y.H., Liang, C.L., and Liu, H.Y. (2023). An overview of Fructus Meliae Toosendan: Botany, traditional uses, phytochemistry, pharmacology and toxicology. Biomed. Pharmacother., 157.","DOI":"10.1016\/j.biopha.2022.113795"},{"key":"ref_4","first-page":"4059","article-title":"Research progress on chemical constituents, pharmacological action and toxicity of Melia toosendan","volume":"51","author":"Li","year":"2020","journal-title":"Chin. Tradit. Herb. Drugs"},{"key":"ref_5","first-page":"1820","article-title":"Study on rapid screening and identifying hepatotoxic compounds in Toosendan Fructus","volume":"38","author":"Zhao","year":"2013","journal-title":"Zhongguo Zhongyao Zazhi"},{"key":"ref_6","first-page":"161","article-title":"The pharmacological effect and its underlying mcchanisms of toosendanin: A review","volume":"32","author":"Luo","year":"2016","journal-title":"Pharmacol. Clin. Chin. Mater. Medica"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jin, Y.H., Kwon, S., Choi, J.G., Cho, W.K., Lee, B., and Ma, J.Y. (2019). Toosendanin From Melia Fructus Suppresses Influenza A Virus Infection by Altering Nuclear Localization of Viral Polymerase PA Protein. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01025"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1080\/10286020.2018.1451516","article-title":"Anti-cancer effect of toosendanin and its underlying mechanisms","volume":"21","author":"Zhang","year":"2019","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41401-018-0024-8","article-title":"Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2\/GCL\/GSH antioxidant signaling pathway","volume":"40","author":"Jin","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Luo, L., Liang, Y., Fu, Y., Liang, Z., Zheng, J., Lan, J., Shen, F., and Huang, Z. (2022). Toosendanin Induces Hepatocyte Damage by Inhibiting Autophagic Flux via TFEB-Mediated Lysosomal Dysfunction. Pharmaceuticals, 15.","DOI":"10.3390\/ph15121509"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114631","DOI":"10.1016\/j.fct.2024.114631","article-title":"Toosendanin induces hepatotoxicity via disrupting LXR\u03b1\/Lipin1\/SREBP1 mediated lipid metabolism","volume":"187","author":"Chen","year":"2024","journal-title":"Food Chem. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1080\/01480545.2023.2295230","article-title":"Ferroptosis: Action and mechanism of chemical\/drug-induced liver injury","volume":"47","author":"Zeng","year":"2024","journal-title":"Drug Chem. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., and Vergely, C. (2022). Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010449"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1021\/acscentsci.7b00589","article-title":"Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis","volume":"4","author":"Shah","year":"2018","journal-title":"ACS Cent. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.toxlet.2023.02.006","article-title":"Toosendanin induced hepatotoxicity via triggering PERK-eIF2\u03b1-ATF4 mediated ferroptosis","volume":"377","author":"Liang","year":"2023","journal-title":"Toxicol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/asia.201901461","article-title":"EPR Spectroscopic Studies of Lipoxygenases","volume":"15","author":"Gaffney","year":"2020","journal-title":"Chem. Asian J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Reichert, C.O., de Freitas, F.A., Sampaio-Silva, J., Rokita-Rosa, L., Barros, P.d.L., Levy, D., and Bydlowski, S.P. (2020). Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228765"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1021\/cr200246d","article-title":"Lipoxygenase and leukotriene pathways: Biochemistry, biology, and roles in disease","volume":"111","author":"Funk","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106779","DOI":"10.1016\/j.phrs.2023.106779","article-title":"ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis","volume":"193","author":"Li","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/bph.13336","article-title":"Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity","volume":"173","author":"Pu","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1016\/j.apsb.2024.05.014","article-title":"Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-mediated modulation of hepatic lipid metabolism","volume":"14","author":"Li","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/ncb3064","article-title":"Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice","volume":"16","author":"Schneider","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cmet.2008.07.005","article-title":"Glutathione peroxidase 4 senses and translates oxidative stress into 12\/15-lipoxygenase dependent- and AIF-mediated cell death","volume":"8","author":"Seiler","year":"2008","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Onodera, T., Fukuhara, A., Shin, J., Hayakawa, T., Otsuki, M., and Shimomura, I. (2017). Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-04474-2"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1128\/JVI.73.6.4755-4766.1999","article-title":"Implication of interfering antibody formation and apoptosis as two different mechanisms leading to variable duration of adenovirus-mediated transgene expression in immune-competent mice","volume":"73","author":"Schowalter","year":"1999","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2841","DOI":"10.1038\/cddis.2017.236","article-title":"Brg1-mediated Nrf2\/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury","volume":"8","author":"Ge","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3: The human gene integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1.2.1","DOI":"10.1002\/cpbi.27","article-title":"Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes","volume":"58","author":"Amberger","year":"2017","journal-title":"Curr. Protoc. Bioinform."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1078\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:13:34Z","timestamp":1760033614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,21]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18071078"],"URL":"https:\/\/doi.org\/10.3390\/ph18071078","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,21]]}}}