{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:53:54Z","timestamp":1787003634442,"version":"build-2736575974"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Natural Science Foundation of Ningbo Municipality","award":["2024J343"],"award-info":[{"award-number":["2024J343"]}]},{"name":"Natural Science Foundation of Ningbo Municipality","award":["20221JCGY010080"],"award-info":[{"award-number":["20221JCGY010080"]}]},{"name":"Natural Science Foundation of Ningbo Municipality","award":["2023J158"],"award-info":[{"award-number":["2023J158"]}]},{"name":"Ningbo Medical Science and Technology Project","award":["2021Y06"],"award-info":[{"award-number":["2021Y06"]}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQ20H160008"],"award-info":[{"award-number":["LQ20H160008"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical and Health Science and Technology Program of Zhejiang Province","award":["2023KY258"],"award-info":[{"award-number":["2023KY258"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-00909-3","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T02:21:26Z","timestamp":1746584486000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sinularin induces autophagy-dependent cell death by activating ULK1 and enhancing FOXO3-ATG4A axis in prostate cancer cells"],"prefix":"10.1038","volume":"15","author":[{"given":"Xiang-yu","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-jun","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha-zhou","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"issue":"9","key":"909_CR1","doi-asserted-by":"publisher","first-page":"488","DOI":"10.3390\/md19090488","volume":"19","author":"L Wu","year":"2021","unstructured":"Wu, L., Ye, K., Jiang, S. & Zhou, G. Marine power on cancer: drugs, lead compounds, and mechanisms. Mar. Drugs. 19 (9), 488 (2021).","journal-title":"Mar. Drugs"},{"issue":"1","key":"909_CR2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bph.14876","volume":"177","author":"PC Jimenez","year":"2020","unstructured":"Jimenez, P. C. et al. Enriching cancer Pharmacology with drugs of marine origin. Br. J. Pharmacol. 177 (1), 3\u201327 (2020).","journal-title":"Br. J. Pharmacol."},{"issue":"18","key":"909_CR3","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1007\/s40265-018-1022-3","volume":"78","author":"HA Blair","year":"2018","unstructured":"Blair, H. A. Daunorubicin\/Cytarabine liposome: A review in acute myeloid leukaemia. Drugs 78 (18), 1903\u20131910 (2018).","journal-title":"Drugs"},{"issue":"7","key":"909_CR4","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/j.jtha.2023.04.005","volume":"21","author":"JH Levy","year":"2023","unstructured":"Levy, J. H., Ghadimi, K., Kizhakkedathu, J. N. & Iba, T. What\u2019s fishy about Protamine?? Clinical use, adverse reactions, and potential alternatives. J. Thromb. Haemost. 21 (7), 1714\u20131723 (2023).","journal-title":"J. Thromb. Haemost"},{"issue":"4","key":"909_CR5","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.bcp.2013.12.025","volume":"87","author":"R Seifert","year":"2014","unstructured":"Seifert, R. Vidarabine is neither a potent nor a selective AC5 inhibitor. Biochem. Pharmacol. 87 (4), 543\u2013546 (2014).","journal-title":"Biochem. Pharmacol."},{"key":"909_CR6","doi-asserted-by":"publisher","first-page":"111091","DOI":"10.1016\/j.biopha.2020.111091","volume":"134","author":"AFUH Saeed","year":"2021","unstructured":"Saeed, A. F. U. H., Su, J. & Ouyang, S. Marine-derived drugs: recent advances in cancer therapy and immune signaling. Biomed. Pharmacother. 134, 111091 (2021).","journal-title":"Biomed. Pharmacother"},{"issue":"7","key":"909_CR7","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1002\/elps.201100462","volume":"33","author":"TR Su","year":"2012","unstructured":"Su, T. R. et al. Proteomic investigation of anti-tumor activities exerted by sinularin against A2058 melanoma cells. Electrophoresis 33 (7), 1139\u20131152 (2012).","journal-title":"Electrophoresis"},{"issue":"8","key":"909_CR8","doi-asserted-by":"publisher","first-page":"142","DOI":"10.3390\/md14080142","volume":"14","author":"YJ Wu","year":"2016","unstructured":"Wu, Y. J., Wong, B. S., Yea, S. H., Lu, C. I. & Weng, S. H. Sinularin induces apoptosis through mitochondria dysfunction and inactivation of the pI3K\/Akt\/mTOR pathway in gastric carcinoma cells. Mar. Drugs. 14 (8), 142 (2016).","journal-title":"Mar. Drugs"},{"issue":"9","key":"909_CR9","doi-asserted-by":"publisher","first-page":"2124","DOI":"10.1002\/tox.22425","volume":"32","author":"YT Chang","year":"2017","unstructured":"Chang, Y. T. et al. Sinularin induces oxidative stress-mediated G2\/M arrest and apoptosis in oral cancer cells. Environ. Toxicol. 32 (9), 2124\u20132132 (2017).","journal-title":"Environ. Toxicol."},{"issue":"10","key":"909_CR10","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.3390\/cancers13102450","volume":"13","author":"SY Peng","year":"2021","unstructured":"Peng, S. Y. et al. Oxidative Stress-Dependent synergistic antiproliferation, apoptosis, and DNA damage of Ultraviolet-C and Coral-Derived sinularin combined treatment for oral Cancer cells. Cancers (Basel). 13 (10), 2450 (2021).","journal-title":"Cancers (Basel)"},{"issue":"10","key":"909_CR11","doi-asserted-by":"publisher","first-page":"994","DOI":"10.3390\/ph14100994","volume":"14","author":"KH Yang","year":"2021","unstructured":"Yang, K. H. et al. Soft Coral-Derived Dihydrosinularin exhibits antiproliferative effects associated with apoptosis and DNA damage in oral Cancer cells. Pharmaceuticals (Basel). 14 (10), 994 (2021).","journal-title":"Pharmaceuticals (Basel)"},{"issue":"8","key":"909_CR12","doi-asserted-by":"publisher","first-page":"3946","DOI":"10.3390\/ijms22083946","volume":"22","author":"CY Ko","year":"2021","unstructured":"Ko, C. Y. et al. Sinularin, an Anti-Cancer agent causing Mitochondria-Modulated apoptosis and cytoskeleton disruption in human hepatocellular carcinoma. Int. J. Mol. Sci. 22 (8), 3946 (2021).","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"909_CR13","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s12906-017-1583-9","volume":"17","author":"TW Chung","year":"2017","unstructured":"Chung, T. W. et al. Sinularin induces DNA damage, G2\/M phase arrest, and apoptosis in human hepatocellular carcinoma cells. BMC Complement. Altern. Med. 17 (1), 62 (2017).","journal-title":"BMC Complement. Altern. Med."},{"issue":"4","key":"909_CR14","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3390\/molecules23040849","volume":"23","author":"HW Huang","year":"2018","unstructured":"Huang, H. W. et al. Sinularin selectively kills breast Cancer cells showing G2\/M arrest, apoptosis, and oxidative DNA damage. Molecules 23 (4), 849 (2018).","journal-title":"Molecules"},{"key":"909_CR15","doi-asserted-by":"publisher","first-page":"5886269","DOI":"10.1155\/2022\/5886269","volume":"2022","author":"R Hossain","year":"2022","unstructured":"Hossain, R. et al. Natural compounds or their derivatives against breast cancer: A computational study. Biomed. Res. Int. 2022, 5886269 (2022).","journal-title":"Biomed. Res. Int."},{"issue":"13","key":"909_CR16","doi-asserted-by":"publisher","first-page":"3853","DOI":"10.3390\/molecules26133853","volume":"26","author":"SC Wang","year":"2021","unstructured":"Wang, S. C. et al. Comparison of antioxidant and anticancer properties of soft Coral-Derived sinularin and Dihydrosinularin. Molecules 26 (13), 3853 (2021).","journal-title":"Molecules"},{"issue":"21","key":"909_CR17","doi-asserted-by":"publisher","first-page":"5114","DOI":"10.7150\/jca.31232","volume":"10","author":"Q Ma","year":"2019","unstructured":"Ma, Q. et al. Sinularin exerts anti-tumor effects against human renal cancer cells relies on the generation of ROS. J. Cancer. 10 (21), 5114\u20135123 (2019).","journal-title":"J. Cancer"},{"key":"909_CR18","doi-asserted-by":"publisher","first-page":"116011","DOI":"10.1016\/j.bcp.2023.116011","volume":"220","author":"XY Meng","year":"2024","unstructured":"Meng, X. Y. et al. Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis. Biochem. Pharmacol. 220, 116011 (2024).","journal-title":"Biochem. Pharmacol."},{"issue":"4","key":"909_CR19","first-page":"1286","volume":"11","author":"XY Meng","year":"2021","unstructured":"Meng, X. Y. et al. Pinin promotes tumor progression via activating CREB through PI3K\/AKT and ERK\/MAPK pathway in prostate cancer. Am. J. Cancer Res. 11 (4), 1286\u20131303 (2021).","journal-title":"Am. J. Cancer Res."},{"issue":"9","key":"909_CR20","first-page":"5575","volume":"12","author":"X Meng","year":"2020","unstructured":"Meng, X. et al. MiR-125b-2-3p associates with prognosis of CcRCC through promoting tumor metastasis via targeting EGR1. Am. J. Transl Res. 12 (9), 5575\u20135585 (2020).","journal-title":"Am. J. Transl Res."},{"issue":"16","key":"909_CR21","doi-asserted-by":"publisher","first-page":"6642","DOI":"10.18632\/aging.204236","volume":"14","author":"L Ma","year":"2022","unstructured":"Ma, L. et al. Rhein promotes TRAIL-induced apoptosis in bladder cancer cells by up-regulating DR5 expression. Aging (Albany NY). 14 (16), 6642\u20136655 (2022).","journal-title":"Aging (Albany NY)"},{"issue":"7","key":"909_CR22","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1517\/14728222.2015.1053208","volume":"19","author":"X Wang","year":"2015","unstructured":"Wang, X. et al. Decrease of phosphorylated proto-oncogene CREB at Ser 133 site inhibits growth and metastatic activity of renal cell cancer. Expert Opin. Ther. Targets. 19 (7), 985\u2013995 (2015).","journal-title":"Expert Opin. Ther. Targets"},{"issue":"7","key":"909_CR23","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41568-022-00459-0","volume":"22","author":"G Lei","year":"2022","unstructured":"Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer. 22 (7), 381\u2013396 (2022).","journal-title":"Nat. Rev. Cancer"},{"issue":"1","key":"909_CR24","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","volume":"8","author":"V Panwar","year":"2023","unstructured":"Panwar, V. et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal. Transduct. Target. Ther. 8 (1), 375 (2023).","journal-title":"Signal. Transduct. Target. Ther."},{"issue":"2","key":"909_CR25","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/ncb2152","volume":"13","author":"J Kim","year":"2011","unstructured":"Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell. Biol. 13 (2), 132\u2013141 (2011).","journal-title":"Nat. Cell. Biol."},{"issue":"1","key":"909_CR26","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41573-020-0088-2","volume":"20","author":"G Calissi","year":"2021","unstructured":"Calissi, G., Lam, E. W. & Link, W. Therapeutic strategies targeting FOXO transcription factors. Nat. Rev. Drug Discov. 20 (1), 21\u201338 (2021).","journal-title":"Nat. Rev. Drug Discov"},{"issue":"D1","key":"909_CR27","first-page":"D87","volume":"48","author":"O Fornes","year":"2020","unstructured":"Fornes, O. et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48 (D1), D87\u2013D92 (2020).","journal-title":"Nucleic Acids Res."},{"issue":"12","key":"909_CR28","doi-asserted-by":"publisher","first-page":"3579","DOI":"10.1182\/bloodadvances.2021005910","volume":"6","author":"MC Stolla","year":"2022","unstructured":"Stolla, M. C. et al. ATG4A regulates human erythroid maturation and mitochondrial clearance. Blood Adv. 6 (12), 3579\u20133589 (2022).","journal-title":"Blood Adv."},{"issue":"9","key":"909_CR29","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.3390\/cells11091479","volume":"11","author":"M Sorice","year":"2022","unstructured":"Sorice, M. Crosstalk of autophagy and apoptosis. Cells 11 (9), 1479 (2022).","journal-title":"Cells"},{"issue":"9\u201310","key":"909_CR30","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1007\/s10495-021-01687-9","volume":"26","author":"S Das","year":"2021","unstructured":"Das, S., Shukla, N., Singh, S. S., Kushwaha, S. & Shrivastava, R. Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis 26 (9\u201310), 512\u2013533 (2021).","journal-title":"Apoptosis"},{"issue":"12","key":"909_CR31","doi-asserted-by":"publisher","first-page":"21575","DOI":"10.1002\/jcp.28784","volume":"234","author":"P Zafari","year":"2019","unstructured":"Zafari, P., Rafiei, A., Esmaeili, S. A., Moonesi, M. & Taghadosi, M. Survivin a pivotal antiapoptotic protein in rheumatoid arthritis. J. Cell. Physiol. 234 (12), 21575\u201321587 (2019).","journal-title":"J. Cell. Physiol."},{"issue":"3","key":"909_CR32","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/med.21547","volume":"39","author":"D Mart\u00ednez-Garc\u00eda","year":"2019","unstructured":"Mart\u00ednez-Garc\u00eda, D., Manero-Rup\u00e9rez, N., Quesada, R., Korrodi-Greg\u00f3rio, L. & Soto-Cerrato, V. Therapeutic strategies involving survivin Inhibition in cancer. Med. Res. Rev. 39 (3), 887\u2013909 (2019).","journal-title":"Med. Res. Rev."},{"issue":"4","key":"909_CR33","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/S0960-9822(03)00082-4","volume":"13","author":"SM Gorski","year":"2003","unstructured":"Gorski, S. M. et al. A SAGE approach to discovery of genes involved in autophagic cell death. Curr. Biol. 13 (4), 358\u2013363 (2003).","journal-title":"Curr. Biol."},{"issue":"4","key":"909_CR34","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","volume":"147","author":"N Mizushima","year":"2011","unstructured":"Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147 (4), 728\u2013741 (2011).","journal-title":"Cell"},{"issue":"1\u20132","key":"909_CR35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","volume":"176","author":"B Levine","year":"2019","unstructured":"Levine, B. & Kroemer, G. Biological functions of autophagy genes: A disease perspective. Cell 176 (1\u20132), 11\u201342 (2019).","journal-title":"Cell"},{"issue":"6","key":"909_CR36","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/nrendo.2014.35","volume":"10","author":"KH Kim","year":"2014","unstructured":"Kim, K. H. & Lee, M. S. Autophagy\u2013a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10 (6), 322\u2013337 (2014).","journal-title":"Nat. Rev. Endocrinol."},{"issue":"9","key":"909_CR37","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/nrc.2017.53","volume":"17","author":"JMM Levy","year":"2017","unstructured":"Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer. 17 (9), 528\u2013542 (2017).","journal-title":"Nat. Rev. Cancer"},{"issue":"6","key":"909_CR38","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1042\/EBC20170021","volume":"61","author":"M Zachari","year":"2017","unstructured":"Zachari, M. & Ganley, I. G. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 61 (6), 585\u2013596 (2017).","journal-title":"Essays Biochem."},{"issue":"1","key":"909_CR39","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1172\/JCI73939","volume":"125","author":"YC Kim","year":"2015","unstructured":"Kim, Y. C. & Guan, K. L. mTOR: a Pharmacologic target for autophagy regulation. J. Clin. Invest. 125 (1), 25\u201332 (2015).","journal-title":"J. Clin. Invest."},{"issue":"4","key":"909_CR40","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","volume":"21","author":"GY Liu","year":"2020","unstructured":"Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell. Biol. 21 (4), 183\u2013203 (2020).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"issue":"9","key":"909_CR41","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1016\/j.molcel.2021.03.001","volume":"81","author":"TN Nguyen","year":"2021","unstructured":"Nguyen, T. N. et al. ATG4 family proteins drive phagophore growth independently of the LC3\/GABARAP lipidation system. Mol. Cell. 81 (9), 2013\u20132030e9 (2021).","journal-title":"Mol. Cell."},{"key":"909_CR42","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12943-015-0321-5","volume":"14","author":"Z Su","year":"2015","unstructured":"Su, Z., Yang, Z., Xu, Y., Chen, Y. & Yu, Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol. Cancer. 14, 48 (2015).","journal-title":"Mol. Cancer"},{"issue":"12","key":"909_CR43","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.2174\/1871520623666230331083744","volume":"23","author":"Z Wu","year":"2023","unstructured":"Wu, Z. et al. Sinularin exerts Anti-cancer effects by inducing oxidative Stress-mediated ferroptosis, apoptosis, and autophagy in prostate Cancer cells. Anticancer Agents Med. Chem. 23 (12), 1457\u20131468 (2023).","journal-title":"Anticancer Agents Med. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-00909-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-00909-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-00909-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T03:02:21Z","timestamp":1746586941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-00909-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,7]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["909"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-00909-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,7]]},"assertion":[{"value":"4 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 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"}},{"value":"All authors consent this manuscript for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"15875"}}