{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:12:52Z","timestamp":1791497572307,"version":"4.3.4"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Scientific Research Foundation of Guiyang Healthcare Vocational University","award":["Guikangda K2024-5"],"award-info":[{"award-number":["Guikangda K2024-5"]}]},{"name":"Scientific Research Foundation of Guiyang Healthcare Vocational University","award":["Guikangda K2024-9"],"award-info":[{"award-number":["Guikangda K2024-9"]}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Science and Technology Department","doi-asserted-by":"crossref","award":["ZK [2022]459"],"award-info":[{"award-number":["ZK [2022]459"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guizhou Provincial Administration of Traditional Chinese Medicine and Ethnic Medicine Science and Technology Research Project","award":["QZYY-2025-086"],"award-info":[{"award-number":["QZYY-2025-086"]}]},{"name":"Guizhou Provincial Basic Research Program","award":["QKHJC MS\u30142025\u3015516"],"award-info":[{"award-number":["QKHJC MS\u30142025\u3015516"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81960635"],"award-info":[{"award-number":["81960635"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Hepatocellular carcinoma (HCC) remains a significant global health challenge, with drug therapy being a critical treatment approach. However, the development of drug resistance and the occurrence of adverse reactions to existing medications have made the creation of new HCC treatments urgent. Tetrandrine, a bisbenzylisoquinoline alkaloid from natural products, has shown great potential in this area. Yet, systematic comparative studies on different tetrandrine modification sites (such as C-7 and C-14) are lacking, which has hindered the simultaneous optimization of its antitumor activity and synthetic feasibility. In this study, we focused on a C-7 modification strategy and designed and synthesized 38 novel tetrandrine sulfonate derivatives (including 31 new compounds) through an efficient one-step reaction. The in vitro antiproliferative activities of these derivatives were evaluated against four HCC cell lines (HepG-2, SMMC-7721, SK-Hep-1, and QGY-7701), and a systematic comparison with previously reported C-14 sulfonate derivatives was conducted. The results showed that all the C-7 derivatives exhibited good antiproliferative activities against HCC. Notably, compound <jats:bold>15<\/jats:bold> demonstrated significant antiproliferative activity against all tested cell lines, with IC<jats:sub>50<\/jats:sub> values ranging from 3.28 to 6.16 \u00b5M, which is superior to the first-line clinical drug 5-fluorouracil. Mechanistic studies revealed that compound <jats:bold>15<\/jats:bold> exerts its antitumor effects by regulating the balance of Bcl-2 and Bax proteins, triggering the release of cytochrome C from mitochondria, and subsequently activating the caspase-3-dependent apoptosis pathway. The results of target prediction showed that PDGFRA, FLT1, PIK3CD and MET might be the main targets of compound <jats:bold>15<\/jats:bold> against hepatocellular carcinoma. Although C-14 sulfonate derivatives showed slightly higher in vitro activity, C-7 derivatives (particularly compound <jats:bold>15<\/jats:bold>) exhibited significant advantages in synthetic efficiency (one-step reaction), ease of purification, environmental friendliness, and scalability for industrial production. In conclusion, this study has established C-7 sulfonation as an efficient strategy for developing tetrandrine-based anti-HCC agents. With its remarkable antitumor activity, excellent synthetic process characteristics, and clear apoptosis-inducing mechanism, compound <jats:bold>15<\/jats:bold> has emerged as a highly promising clinical candidate. This C-7 modification platform provides a viable path for transforming natural product derivatives into clinical therapies for HCC treatment.<\/jats:p>","DOI":"10.1038\/s41598-025-18875-1","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:14:40Z","timestamp":1759158880000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating C7 modified tetrandrine derivatives for synthesis anti-hepatocellular carcinoma activity and mechanistic insights"],"prefix":"10.1038","volume":"15","author":[{"given":"Taibai","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueke","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"18875_CR1","doi-asserted-by":"crossref","unstructured":"Siegel, R. L., Giaquinto, A. N., Jemal, A. & Cancer Statistics CA A Cancer J Clinicians 2024, 74, 12\u201349. (2024).","DOI":"10.3322\/caac.21820"},{"key":"18875_CR2","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","volume":"20","author":"AG Singal","year":"2023","unstructured":"Singal, A. G., Kanwal, F. & Llovet, J. M. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat. Rev. Clin. Oncol. 20, 864\u2013884 (2023).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"18875_CR3","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","volume":"400","author":"A Vogel","year":"2022","unstructured":"Vogel, A., Meyer, T., Sapisochin, G., Salem, R. & Saborowski, A. Hepatocellular carcinoma. Lancet 400, 1345\u20131362 (2022).","journal-title":"Lancet"},{"key":"18875_CR4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","volume":"10","author":"JJ Zheng","year":"2025","unstructured":"Zheng, J. J. et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Sig Transduct. Target. Ther. 10, 35 (2025).","journal-title":"Sig Transduct. Target. Ther."},{"key":"18875_CR5","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.annonc.2021.02.014","volume":"32","author":"A Vogel","year":"2021","unstructured":"Vogel, A. et al. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO clinical practice guidelines. Ann. Oncol. 32, 801\u2013805 (2021).","journal-title":"Ann. Oncol."},{"key":"18875_CR6","doi-asserted-by":"publisher","first-page":"3202","DOI":"10.3390\/biomedicines10123202","volume":"10","author":"D T\u00fcmen","year":"2022","unstructured":"T\u00fcmen, D. et al. Pathogenesis and current treatment strategies of hepatocellular carcinoma. Biomedicines 10, 3202 (2022).","journal-title":"Biomedicines"},{"key":"18875_CR7","doi-asserted-by":"publisher","first-page":"5232","DOI":"10.3390\/ijms21155232","volume":"21","author":"J Gong","year":"2020","unstructured":"Gong, J. et al. Molecular targets, pathways, and therapeutic implications for hepatocellular carcinoma. Int. J. Mol. Sci. 21, 5232 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"18875_CR8","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1080\/14728222.2021.1976142","volume":"25","author":"HC Wang","year":"2021","unstructured":"Wang, H. C., Chen, X. & Calvisi, D. F. Hepatocellular carcinoma (HCC): the most promising therapeutic targets in the preclinical arena based on tumor biology characteristics. Expert Opin. Ther. Targets. 25, 645\u2013658 (2021).","journal-title":"Expert Opin. Ther. Targets"},{"key":"18875_CR9","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1001\/jamaoncol.2023.2677","volume":"10","author":"S Cappuyns","year":"2024","unstructured":"Cappuyns, S., Corbett, V., Yarchoan, M., Finn, R. S. & Llovet, J. M. Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma: A review. JAMA Oncol. 10, 395 (2024).","journal-title":"JAMA Oncol."},{"key":"18875_CR10","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.jhep.2021.11.030","volume":"76","author":"AL Cheng","year":"2022","unstructured":"Cheng, A. L. et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. Sorafenib for unresectable hepatocellular carcinoma. J. Hepatol. 76, 862\u2013873 (2022).","journal-title":"J. Hepatol."},{"key":"18875_CR11","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1016\/S1470-2045(23)00469-2","volume":"24","author":"JM Llovet","year":"2023","unstructured":"Llovet, J. M. et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): A randomised, Double-Blind, phase 3 trial. Lancet Oncol. 24, 1399\u20131410 (2023).","journal-title":"Lancet Oncol."},{"key":"18875_CR12","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s40265-019-01116-x","volume":"79","author":"ZT Al-Salama","year":"2019","unstructured":"Al-Salama, Z. T., Syed, Y. Y., Scott, L. J. & Lenvatinib A review in hepatocellular carcinoma. Drugs 79, 665\u2013674 (2019).","journal-title":"Drugs"},{"key":"18875_CR13","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/s41591-024-02824-y","volume":"30","author":"HD Kim","year":"2024","unstructured":"Kim, H. D. et al. Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial. Nat. Med. 30, 699\u2013707 (2024).","journal-title":"Nat. Med."},{"key":"18875_CR14","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1080\/14740338.2022.1995353","volume":"21","author":"CC Yen","year":"2022","unstructured":"Yen, C. C. & Yen, C. J. Safety of ramucirumab treatment in patients with advanced hepatocellular carcinoma and elevated Alpha-Fetoprotein. Expert Opin. Drug Saf. 21, 157\u2013166 (2022).","journal-title":"Expert Opin. Drug Saf."},{"key":"18875_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.acr.2020.10.001","volume":"149","author":"S Chidambaranathan Reghupaty","year":"2021","unstructured":"Chidambaranathan Reghupaty, S., Fisher, P. B. & Sarkar, D. Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv. Cancer Res. 149, 1\u201361 (2021).","journal-title":"Adv. Cancer Res."},{"key":"18875_CR16","doi-asserted-by":"publisher","first-page":"087","DOI":"10.1055\/s-0041-1735631","volume":"42","author":"JJG Marin","year":"2022","unstructured":"Marin, J. J. G. et al. Mechanisms of pharmacoresistance in hepatocellular carcinoma: new drugs but old problems. Semin Liver Dis. 42, 087\u2013103 (2022).","journal-title":"Semin Liver Dis."},{"key":"18875_CR17","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/S1470-2045(22)00326-6","volume":"23","author":"RK Kelley","year":"2022","unstructured":"Kelley, R. K. et al. Cabozantinib plus Atezolizumab versus Sorafenib for advanced hepatocellular carcinoma (COSMIC-312): A multicentre, Open-Label, randomised, phase 3 trial. Lancet Oncol. 23, 995\u20131008 (2022).","journal-title":"Lancet Oncol."},{"key":"18875_CR18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s13659-020-00293-7","volume":"11","author":"M Huang","year":"2021","unstructured":"Huang, M., Lu, J. J. & Ding, J. Natural products in cancer therapy: past, present and future. Nat. Prod. Bioprospect. 11, 5\u201313 (2021).","journal-title":"Nat. Prod. Bioprospect"},{"key":"18875_CR19","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","volume":"83","author":"DJ Newman","year":"2020","unstructured":"Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019. J. Nat. Prod. 83, 770\u2013803 (2020).","journal-title":"J. Nat. Prod."},{"key":"18875_CR20","doi-asserted-by":"publisher","first-page":"8367","DOI":"10.3390\/molecules27238367","volume":"27","author":"A Naeem","year":"2022","unstructured":"Naeem, A. et al. Natural products as anticancer agents: current status and future perspectives. Molecules 27, 8367 (2022).","journal-title":"Molecules"},{"key":"18875_CR21","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","volume":"20","author":"AG Atanasov","year":"2021","unstructured":"Atanasov, A. G. et al. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200\u2013216 (2021).","journal-title":"Nat. Rev. Drug Discov"},{"key":"18875_CR22","doi-asserted-by":"publisher","first-page":"108752","DOI":"10.1016\/j.pharmthera.2024.108752","volume":"264","author":"YX Wang","year":"2024","unstructured":"Wang, Y. X. et al. New drug discovery and development from natural products: advances and strategies. Pharmacol. Ther. 264, 108752 (2024).","journal-title":"Pharmacol. Ther."},{"issue":"2","key":"18875_CR23","first-page":"163","volume":"3","author":"ZS Wang","year":"2024","unstructured":"Wang, Z. S., Liu, Z. C., Qu, J., Sun, Y. & Zhou, W. C. Role of natural products in tumor therapy from basic research and clinical perspectives. Acta Materia Med. 3 (2), 163\u2013206 (2024).","journal-title":"Acta Materia Med."},{"key":"18875_CR24","doi-asserted-by":"publisher","first-page":"113566","DOI":"10.1016\/j.jep.2020.113566","volume":"268","author":"H Zhang","year":"2021","unstructured":"Zhang, H. et al. Thirteen bisbenzylisoquinoline alkaloids in five Chinese medicinal plants: botany, traditional uses, phytochemistry, Pharmacokinetic and toxicity studies. J. Ethnopharmacol. 268, 113566 (2021).","journal-title":"J. Ethnopharmacol."},{"key":"18875_CR25","doi-asserted-by":"publisher","first-page":"112727","DOI":"10.1016\/j.biopha.2022.112727","volume":"148","author":"N Bhagya","year":"2022","unstructured":"Bhagya, N. & Chandrashekar, K. R. Autophagy and cancer: can tetrandrine be a potent anticancer drug in the near future? Biomed. Pharmacother. 148, 112727 (2022).","journal-title":"Biomed. Pharmacother."},{"key":"18875_CR26","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1007\/s10787-024-01452-9","volume":"32","author":"JW Song","year":"2024","unstructured":"Song, J. W. et al. Therapeutic effects of tetrandrine in inflammatory diseases: A comprehensive review. Inflammopharmacol 32, 1743\u20131757 (2024).","journal-title":"Inflammopharmacol"},{"key":"18875_CR27","doi-asserted-by":"publisher","first-page":"112995","DOI":"10.1016\/j.jep.2020.112995","volume":"260","author":"YL Zhang","year":"2020","unstructured":"Zhang, Y. L. et al. History of uses, phytochemistry, Pharmacological activities, quality control and toxicity of the root of Stephania Tetrandra S. Moore: A review. J. Ethnopharmacol. 260, 112995 (2020).","journal-title":"J. Ethnopharmacol."},{"issue":"9","key":"18875_CR28","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1080\/10286020.2013.823950","volume":"15","author":"CZ Wu","year":"2013","unstructured":"Wu, C. Z., Lai, L., Hu, X., Lei, R. R. & Yang, Y. F. Synthesis and antitumor activity of tetrandrine derivatives[J]. J. Asian Nat. Prod. Res. 15 (9), 993\u20131002 (2013).","journal-title":"J. Asian Nat. Prod. Res."},{"issue":"10","key":"18875_CR29","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1080\/10286020.2016.1188085","volume":"18","author":"X Wei","year":"2016","unstructured":"Wei, X. et al. Design and synthesis of new tetrandrine derivatives and their antitumor activities[J]. J. Asian Nat. Prod. Res. 18 (10), 966\u2013975 (2016).","journal-title":"J. Asian Nat. Prod. Res."},{"issue":"11","key":"18875_CR30","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1080\/10286020.2018.1478817","volume":"20","author":"QH Yang","year":"2018","unstructured":"Yang, Q. H. et al. Synthesis of novel tetrandrine derivatives and their Inhibition against NSCLC A549 cells[J]. J. Asian Nat. Prod. Re. 20 (11), 1064\u20131074 (2018).","journal-title":"J. Asian Nat. Prod. Re"},{"key":"18875_CR31","doi-asserted-by":"publisher","first-page":"104694","DOI":"10.1016\/j.bioorg.2021.104694","volume":"109","author":"XZ Gao","year":"2021","unstructured":"Gao, X. Z. et al. Design, synthesis and in vitro anticancer research of novel tetrandrine and Fangchinoline derivatives[J]. Bioorg. Chem. 109, 104694 (2021).","journal-title":"Bioorg. Chem."},{"key":"18875_CR32","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.ejmech.2017.01.008","volume":"127","author":"JJ Lan","year":"2017","unstructured":"Lan, J. J. et al. 5. Eur. J. Med. Chem. 127, 554\u2013566. (2017).","journal-title":"Eur. J. Med. Chem."},{"key":"18875_CR33","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1016\/j.ejmech.2017.11.007","volume":"143","author":"JJ Lan","year":"2018","unstructured":"Lan, J. J. et al. Design and synthesis of novel C14-Urea-Tetrandrine derivatives with potent Anti-Cancer activity. Eur. J. Med. Chem. 143, 1968\u20131980 (2018).","journal-title":"Eur. J. Med. Chem."},{"key":"18875_CR34","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1039\/C8MD00125A","volume":"9","author":"JR Song","year":"2018","unstructured":"Song, J. R. et al. Synthesis and bioactivity investigation of tetrandrine derivatives as potential Anti-Cancer agents. Med. Chem. Commun. 9, 1131\u20131141 (2018).","journal-title":"Med. Chem. Commun."},{"key":"18875_CR35","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.3390\/molecules25071738","volume":"25","author":"SC Hu","year":"2020","unstructured":"Hu, S. C. et al. Synthesis of novel Tetrandrine-14-l-Amino acid and Tetrandrine-14-l-Amino acid-Urea derivatives as potential Anti-Cancer agents. Molecules 25, 1738 (2020).","journal-title":"Molecules"},{"key":"18875_CR36","doi-asserted-by":"publisher","first-page":"1107824","DOI":"10.3389\/fchem.2022.1107824","volume":"10","author":"TB Jiang","year":"2023","unstructured":"Jiang, T. B. et al. A novel class of C14-Sulfonate-Tetrandrine derivatives as potential chemotherapeutic agents for hepatocellular carcinoma. Front. Chem. 10, 1107824 (2023).","journal-title":"Front. Chem."},{"key":"18875_CR37","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.joim.2021.01.001","volume":"19","author":"EWC Chan","year":"2021","unstructured":"Chan, E. W. C., Wong, S. K. & Chan, H. T. An overview on the chemistry, Pharmacology and anticancer properties of tetrandrine and Fangchinoline (Alkaloids) from Stephania Tetrandra roots. J. Integr. Med. 19, 311\u2013316 (2021).","journal-title":"J. Integr. Med."},{"key":"18875_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.apsb.2021.08.026","volume":"12","author":"JJ Wei","year":"2022","unstructured":"Wei, J. J., Zhao, Y. T., Liang, H. H., Du, W. J. & Wang, L. H. Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy. Acta Pharm. Sin B. 12, 1\u201317 (2022).","journal-title":"Acta Pharm. Sin B"},{"key":"18875_CR39","doi-asserted-by":"crossref","unstructured":"Kanehisa, M., Furumichi, M., Sato, Y., Kawashima, M. & Ishiguro-Watanabe, M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 6 (D1), D587\u2013D592 (2023).","DOI":"10.1093\/nar\/gkac963"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-18875-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-18875-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-18875-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:14:43Z","timestamp":1759158883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-18875-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["18875"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-18875-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"assertion":[{"value":"12 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"33601"}}