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Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with limited therapeutic options. Although\n                      <jats:italic>N<\/jats:italic>\n                      -acetyltransferase 10 (NAT10) is frequently overexpressed in multiple cancers, its functional role and therapeutic potential in ATC remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed integrated approaches including bioinformatics analyses,in vitro and in vivo assays, multi-omics profiling (mRNA-seq, Ribo-seq, tRNA RedaC-seq), and mechanistic studies (ChIP, LC\u2013MS and ubiquitination assays) in ATC cell lines and xenograft models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NAT10 is significantly upregulated in ATC and correlates with poor prognosis. Functional assay demonstrates that NAT10 enhances ATC cell proliferation and invasion in vitro and in vivo. The targeted inhibition of NAT10 using the small molecule inhibitor remodelin effectively suppresses ATC cell growth. Mechanistically, NAT10 forms a positive feedback loop with the transcription factor c-Myc: c-Myc transcriptionally activates NAT10, whereas NAT10 is associated with enhanced translation of c-Myc in conjunction with tRNA ac\n                      <jats:sup>4<\/jats:sup>\n                      C modification. NAT10 depletion reduces global translation efficiency, accompanied by decreased tRNA ac\n                      <jats:sup>4<\/jats:sup>\n                      C levels, and also affects c-Myc protein stability via the deubiquitinase OTUB1. Moreover, combined treatment with remodelin and doxorubicin exhibits synergistic antitumor effects in both in vitro and in vivo models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings identify a NAT10\/c-Myc positive feedback loop associated with tRNA ac\n                      <jats:sup>4<\/jats:sup>\n                      C modification and protein stabilization in ATC. Targeting this regulatory axis with remodelin in combination with doxorubicin may represent a promising therapeutic strategy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                    <jats:p>NAT10 promotes a c-Myc positive feedback loop via tRNA ac\u2074C modification and OTUB1-mediated stabilization, driving ATC progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s11658-026-00977-x","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T22:46:52Z","timestamp":1781218012000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The NAT10\/c-Myc positive feedback loop orchestrates tRNA ac4C modification and OTUB1-mediated protein stabilization to drive anaplastic thyroid carcinoma progression"],"prefix":"10.1186","volume":"31","author":[{"given":"Bo","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"977_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.semcancer.2020.01.005","volume":"61","author":"N Pozdeyev","year":"2020","unstructured":"Pozdeyev N, Rose MM, Bowles DW, Schweppe RE. 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All animal experiments were approved by the Institutional Animal Care and Ethics Committee of Xiangya Hospital, Central South University, on 10 July 2025 (approval number: 2025071029). The local ethics committee operates in accordance with the guidelines of the International Council for Laboratory Animal Science.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors have agreed with publishing this manuscript.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"139"}}