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KU-57788, a selective inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), has shown promise in cancer therapy when combined with radiotherapy and chemotherapy. However, its therapeutic potential and underlying mechanisms in ATC remain unclear. In this study, we demonstrate that KU-57788 exerts potent anti-ATC activity both in vitro and in vivo by inducing DNA damage and triggering mitotic catastrophe. Unexpectedly, we identify a novel mechanism whereby KU-57788 directly binds to and activates dynamin-related protein 1 (DRP1), leading to excessive mitochondrial fission and fragmentation. This process is accompanied by the protective activation of the NRF2\/SLC7A11\/GSH axis, which mitigates the cytotoxic effects of KU-57788. Notably, pharmacological induction of ferroptosis or cystine depletion effectively synergizes with ATC cells to KU-57788, overcoming resistance and promoting ferroptosis. Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2\/SLC7A11\/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC.<\/jats:p>","DOI":"10.1038\/s41419-026-08595-3","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T18:07:43Z","timestamp":1777399663000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct coupling and protective activation of DRP1 by the DNA-PKcs inhibitor KU-57788 synergizes with ferroptosis in anaplastic thyroid cancer cells"],"prefix":"10.1038","volume":"17","author":[{"given":"Lingling","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changtian","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanwan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9575-4192","authenticated-orcid":false,"given":"Yawen","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinpeng","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoni","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8376-3690","authenticated-orcid":false,"given":"Xinxin","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renhao","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8751-2556","authenticated-orcid":false,"given":"Yefeng","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4447-9767","authenticated-orcid":false,"given":"Wenzhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3298-0051","authenticated-orcid":false,"given":"Haifeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-8325","authenticated-orcid":false,"given":"Guowan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanming","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"8595_CR1","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1001\/jamaoncol.2020.3362","volume":"6","author":"A Maniakas","year":"2020","unstructured":"Maniakas A, Dadu R, Busaidy NL, Wang JR, Ferrarotto R, Lu C, et al. 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