{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:19:10Z","timestamp":1791505150177,"version":"4.3.4"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T00:00:00Z","timestamp":1751673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Natural Major Foundation of Shanghai University of Medicine & Health Sciences","award":["SSF-23-17-008"],"award-info":[{"award-number":["SSF-23-17-008"]}]},{"name":"The Outstanding Leaders Training Program of Shanghai Pudong New Area Health Commission","award":["PWRl2023\u201307"],"award-info":[{"award-number":["PWRl2023\u201307"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tanshinone IIA (Tan IIA), a pleiotropic bioactive natural compound, has a general anti-tumor effect, as well as in bladder cancer. However, little is known about its mechanism. This work attempts to explore the mechanism of Tan IIA promoting cuproptosis in bladder cancer cells and the effective targets. Copper concentration and total m6A quantification were determined using test kits. Cell viability was tested by CCK-8. Gene expression was evaluated by western blot or qRT-PCR. The m6A methylation level of FDX1 was detected by methylated RNA immunoprecipitation. FDX1 3\u2032UTR activity was evaluated by luciferase activity assay. YTHDC1 binding to FDX1 was detected by RNA immunoprecipitation assay. Inhibition of tumor growth by Tan IIA was verified using a mouse xenograft tumor model. Tan IIA inhibits cell viability and induces the expression of FDX1 and lip-DLAT, key regulators of cuproptosis, in bladder cancer cells. The copper chelator tetrathiomolybdate weakens the inhibiting effect of Tan IIA on cell viability; while Tan IIA enhances the inhibiting effect of elesclomol-Cu on cell viability. FDX1 knockdown reverses Tan IIA-induced cuproptosis. Tan IIA increases FDX1 m6A modification, which is reversed by S-adenosylhomocysteine, an inhibitor of METTL3\/METTL14, and this event mediates Tan IIA-induced cuproptosis of bladder cancer cells. The effectiveness of SAH in Tan IIA promoting cuproptosis and antitumor utility is demonstrated in a xenograft tumor model. Tan IIA exerts an anti-bladder cancer effect by promoting the cuproptosis of tumor cells, and the possible mechanism is to promote the expression of FDX1 by METTL3\/METTL14-mediated the increasing FDX1 m6A modification.<\/jats:p>","DOI":"10.1093\/toxres\/tfaf123","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T13:18:52Z","timestamp":1755695932000},"source":"Crossref","is-referenced-by-count":7,"title":["Tanshinone IIA promotes METTL3\/METTL14-mediated FDX1 m6A modification to induce cuproptosis in bladder cancer"],"prefix":"10.1093","volume":"14","author":[{"given":"Bo","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]},{"name":"Graduate School of Xinxiang Medical University , No. 688, East Xiangyang Road, Hongqi District, Xinxiang 453003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]},{"name":"Graduate School, Shanghai University of Traditional Chinese Medicine , No. 1200 Cailun Road, Pudong New Area, Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehui","family":"Kong","sequence":"additional","affiliation":[{"name":"Experimental Cellular Therapy Group, University of California San Francisco , No. 1855 Folsom Street, San Francisco, California 94103 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jidong","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqiang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5853-1950","authenticated-orcid":false,"given":"Hua","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital , No.1500 Zhouyuan Road, Pudong New Area, Shanghai 201318 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"2025082009184900900_ref1","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1007\/s43440-023-00507-y","article-title":"Tanshinone IIA targeting cell signaling pathways: a plausible paradigm for cancer therapy","volume":"75","author":"Alam","year":"2023","journal-title":"Pharmacol Rep"},{"key":"2025082009184900900_ref2","doi-asserted-by":"publisher","first-page":"4735","DOI":"10.2147\/DDDT.S266911","article-title":"Pharmacological activity and mechanism of Tanshinone IIA in related diseases","volume":"Volume 14","author":"Guo","year":"2020","journal-title":"Drug Des Devel Ther"},{"key":"2025082009184900900_ref3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.atherosclerosis.2011.06.041","article-title":"Cardiovascular actions and therapeutic potential of tanshinone IIA","volume":"220","author":"Gao","year":"2012","journal-title":"Atherosclerosis."},{"key":"2025082009184900900_ref4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18081616","article-title":"Tanshinone IIA inhibits epithelial-mesenchymal transition in bladder cancer cells via modulation of STAT3-CCL2 Signaling","volume":"18","author":"Huang","year":"2017","journal-title":"Int J Mol Sci"},{"key":"2025082009184900900_ref5","first-page":"627","article-title":"Anticancer effects of tanshinone IIA in bladder urothelial carcinoma by down-regulating aurora a, HIF-1alpha and Bcl-2 both in vitro and in vivo","volume":"37","author":"Xiao","year":"2024","journal-title":"Pak J Pharm Sci"},{"key":"2025082009184900900_ref6","doi-asserted-by":"publisher","first-page":"e2212267","DOI":"10.1002\/adma.202212267","article-title":"Cuproptosis induced by ROS responsive nanoparticles with Elesclomol and copper combined with alphaPD-L1 for enhanced cancer immunotherapy","volume":"35","author":"Guo","year":"2023","journal-title":"Adv Mater"},{"key":"2025082009184900900_ref7","doi-asserted-by":"publisher","first-page":"958368","DOI":"10.3389\/fimmu.2022.958368","article-title":"Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer","volume":"13","author":"Song","year":"2022","journal-title":"Front Immunol"},{"key":"2025082009184900900_ref8","doi-asserted-by":"publisher","first-page":"4911","DOI":"10.1007\/s00210-023-02928-1","article-title":"PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores","volume":"397","author":"Feng","year":"2024","journal-title":"Naunyn Schmiedeberg's Arch Pharmacol"},{"key":"2025082009184900900_ref9","doi-asserted-by":"publisher","first-page":"923737","DOI":"10.3389\/fgene.2022.923737","article-title":"Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Genet"},{"key":"2025082009184900900_ref10","doi-asserted-by":"publisher","first-page":"7926","DOI":"10.1038\/s41598-023-34752-1","article-title":"Prognostic and immunological role of FDX1 in pan-cancer: an in-silico analysis","volume":"13","author":"Liu","year":"2023","journal-title":"Sci Rep"},{"key":"2025082009184900900_ref11","doi-asserted-by":"publisher","first-page":"938134","DOI":"10.3389\/fphar.2022.938134","article-title":"Ferredoxin 1 is a cuproptosis-key gene responsible for tumor immunity and drug sensitivity: a pan-cancer analysis","volume":"13","author":"Yang","year":"2022","journal-title":"Front Pharmacol"},{"key":"2025082009184900900_ref12","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science."},{"key":"2025082009184900900_ref13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41392-020-00450-x","article-title":"The role of m6A modification in the biological functions and diseases","volume":"6","author":"Jiang","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"2025082009184900900_ref14","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12943-019-1109-9","article-title":"Functions of N6-methyladenosine and its role in cancer","volume":"18","author":"He","year":"2019","journal-title":"Mol Cancer"},{"key":"2025082009184900900_ref15","doi-asserted-by":"publisher","first-page":"2971","DOI":"10.1038\/s41388-024-03139-5","article-title":"M(6)a modification of lipoyltransferase 1 inhibits bladder cancer progression by activating cuproptosis","volume":"43","author":"Du","year":"2024","journal-title":"Oncogene."},{"key":"2025082009184900900_ref16","doi-asserted-by":"publisher","first-page":"999823","DOI":"10.3389\/fimmu.2022.999823","article-title":"Cuproptosis-related gene FDX1 expression correlates with the prognosis and tumor immune microenvironment in clear cell renal cell carcinoma","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"2025082009184900900_ref17","doi-asserted-by":"publisher","first-page":"e18655","DOI":"10.1016\/j.heliyon.2023.e18655","article-title":"FDX1 inhibits thyroid cancer malignant progression by inducing cuprotosis","volume":"9","author":"Chen","year":"2023","journal-title":"Heliyon."},{"key":"2025082009184900900_ref18","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s00210-022-02316-1","article-title":"Tanshinone IIA promotes apoptosis by downregulating BCL2 and upregulating TP53 in triple-negative breast cancer","volume":"396","author":"Liu","year":"2023","journal-title":"Naunyn Schmiedeberg's Arch Pharmacol"},{"key":"2025082009184900900_ref19","doi-asserted-by":"publisher","first-page":"15622","DOI":"10.3390\/ijms150915622","article-title":"Potential therapeutic roles of tanshinone IIA in human bladder cancer cells","volume":"15","author":"Chiu","year":"2014","journal-title":"Int J Mol Sci"},{"key":"2025082009184900900_ref20","doi-asserted-by":"publisher","first-page":"6919","DOI":"10.21037\/tcr-20-1963","article-title":"Tanshinone IIA induces autophagy in colon cancer cells through MEK\/ERK\/mTOR pathway","volume":"9","author":"Qian","year":"2020","journal-title":"Transl Cancer Res"},{"key":"2025082009184900900_ref21","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1002\/tox.23388","article-title":"Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis","volume":"37","author":"Ni","year":"2022","journal-title":"Environ Toxicol"},{"key":"2025082009184900900_ref22","doi-asserted-by":"publisher","first-page":"e202201667","DOI":"10.26508\/lsa.202201667","article-title":"Tanshinone functions as a coenzyme that confers gain of function of NQO1 to suppress ferroptosis","volume":"6","author":"Wang","year":"2023","journal-title":"Life Sci Alliance"},{"key":"2025082009184900900_ref23","doi-asserted-by":"publisher","first-page":"114595","DOI":"10.1016\/j.jep.2021.114595","article-title":"Tanshinone IIA alleviates NLRP3 inflammasome-mediated pyroptosis in mycobacterium tuberculosis-(H37Ra-) infected macrophages by inhibiting endoplasmic reticulum stress","volume":"282","author":"Li","year":"2022","journal-title":"J Ethnopharmacol"},{"key":"2025082009184900900_ref24","doi-asserted-by":"publisher","first-page":"e21153","DOI":"10.1016\/j.heliyon.2023.e21153","article-title":"Cuproptosis-related long noncoding RNAs predicts overall survival and reveal immune microenvironment of bladder cancer","volume":"9","author":"Wang","year":"2023","journal-title":"Heliyon."},{"key":"2025082009184900900_ref25","first-page":"2213","article-title":"Exploring the correlation of glycolysis-related chondroitin polymerizing factor (CHPF) with clinical characteristics, immune infiltration, and cuproptosis in bladder cancer","volume":"13","author":"Zhong","year":"2023","journal-title":"Am J Cancer Res"},{"key":"2025082009184900900_ref26","doi-asserted-by":"publisher","first-page":"850","DOI":"10.3389\/fphar.2019.00850","article-title":"Tanshinone IIA exerts anti-inflammatory and immune-regulating effects on vulnerable atherosclerotic plaque partially via the TLR4\/MyD88\/NF-kappaB signal pathway","volume":"10","author":"Chen","year":"2019","journal-title":"Front Pharmacol"},{"key":"2025082009184900900_ref27","doi-asserted-by":"publisher","first-page":"5009","DOI":"10.1111\/bph.17312","article-title":"Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice","volume":"181","author":"Panwar","year":"2024","journal-title":"Br J Pharmacol"},{"key":"2025082009184900900_ref28","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1186\/s12964-024-01743-2","article-title":"Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?","volume":"22","author":"Zhao","year":"2024","journal-title":"Cell Commun Signal"},{"key":"2025082009184900900_ref29","doi-asserted-by":"publisher","first-page":"6523","DOI":"10.1038\/s41467-023-42025-8","article-title":"Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer","volume":"14","author":"Sun","year":"2023","journal-title":"Nat Commun"},{"key":"2025082009184900900_ref30","doi-asserted-by":"publisher","first-page":"110601","DOI":"10.1016\/j.ygeno.2023.110601","article-title":"The FDX1 methylation regulatory mechanism in the malignant phenotype of glioma","volume":"115","author":"Guowei","year":"2023","journal-title":"Genomics."},{"key":"2025082009184900900_ref31","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.2217\/epi-2023-0230","article-title":"METTL3 promotes non-small-cell lung cancer growth and metastasis by inhibiting FDX1 through copper death-associated pri-miR-21-5p maturation","volume":"15","author":"Qian","year":"2023","journal-title":"Epigenomics."},{"key":"2025082009184900900_ref32","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nchembio.1432","article-title":"A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation","volume":"10","author":"Liu","year":"2014","journal-title":"Nat Chem Biol"},{"key":"2025082009184900900_ref33","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13045-020-00951-w","article-title":"Roles of METTL3 in cancer: mechanisms and therapeutic targeting","volume":"13","author":"Zeng","year":"2020","journal-title":"J Hematol Oncol"}],"container-title":["Toxicology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/4\/tfaf123\/64093019\/tfaf123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/4\/tfaf123\/64093019\/tfaf123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T13:18:53Z","timestamp":1755695933000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxres\/article\/doi\/10.1093\/toxres\/tfaf123\/8238591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,5]]},"references-count":33,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7,5]]}},"URL":"https:\/\/doi.org\/10.1093\/toxres\/tfaf123","relation":{},"ISSN":["2045-4538"],"issn-type":[{"value":"2045-4538","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,7,5]]},"article-number":"tfaf123"}}