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Although temozolomide (TMZ) is a cornerstone of GBM treatment, its efficacy is often compromised by inherent or acquired resistance, underscoring the urgent need to uncover molecular mechanisms, discover new therapeutic targets, and develop innovative treatment strategies. In this study, we found an increased formation of filamentous actin (F\u2010actin) within the nuclei of TMZ\u2010resistant GBM cells. We also showed that overexpression of FSCN1 in TMZ\u2010resistant GBM cells promotes F\u2010actin formation and facilitates the repair of DNA double\u2010strand breaks (DSBs). Further investigation revealed a marked decrease in the expression of YTHDC1 in TMZ\u2010resistant GBM cells, which regulates FSCN1 through m6A modification. Additionally, FSCN1 activates the CDC42\/N\u2010WASP\/Arp2\/3 signaling pathway by recruiting FGD1 to activate CDC42\n                    <jats:sup>GTP<\/jats:sup>\n                    , which drives nuclear F\u2010actin formation. Importantly, combining the FSCN1 inhibitor NP\u2010G2\u2010044, with TMZ therapy resulted in stronger anti\u2010tumor effects both in vitro and in vivo. In conclusion, the study demonstrates that nuclear F\u2010actin formation in GBM promotes DSB repair and reveals that targeting FSCN1 with NP\u2010G2\u2010044 could be a promising strategy for enhancing treatment outcomes and improving the prognosis for GBM patients.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513632","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T09:48:29Z","timestamp":1766828909000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Low YTHDC1 Expression Upregulates FSCN1 to Promote Nuclear F\u2010Actin Formation and Facilitate Double\u2010strand DNA Breaks Repair in TMZ\u2010Resistant Glioblastoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Minglong","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and 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