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Previous studies have shown that selective downregulation of the\n                    <jats:italic>MADD<\/jats:italic>\n                    (MAP-kinase-activating death domain-containing protein) gene isoform increases ATC cell susceptibility to TRAIL-induced apoptosis. However, the existence of multiple\n                    <jats:italic>MADD<\/jats:italic>\n                    gene isoforms raised the possibility of functional compensation. This study aimed to definitively evaluate the role of\n                    <jats:italic>MADD<\/jats:italic>\n                    in ATC by employing CRISPR-Cas9 to Cas9 to target exon 3, a conserved exon expressed in all known MADD isoforms, resulting in functional knockout of MADD expression. CRISPR-Cas9-mediated\n                    <jats:italic>MADD<\/jats:italic>\n                    knockout, performed in three ATC cell lines (8505\u00a0C, C643, and HTH7) with distinct mutational backgrounds, significantly impaired ATC cell function in vitro, as indicated by reduced viability, increased apoptosis, decreased migration, and G0\/G1 cell cycle arrest. RNA-seq analysis revealed alterations in genes related to cell survival, proliferation, and metastasis. In the orthotopic ATC mouse model,\n                    <jats:italic>MADD<\/jats:italic>\n                    deletion dramatically suppressed tumor growth, reduced lung metastases, and prolonged survival. Our findings demonstrate that\n                    <jats:italic>MADD<\/jats:italic>\n                    plays a crucial role in ATC cell survival, proliferation, and metastasis. The consistent effects observed across multiple cell lines and in vivo models suggest that\n                    <jats:italic>MADD<\/jats:italic>\n                    may represent a promising therapeutic target for this aggressive malignancy.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-22907-1","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T14:43:07Z","timestamp":1762785787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CRISPR\/Cas9-mediated deletion of MADD induces cell cycle arrest and apoptosis in anaplastic thyroid cancer cells"],"prefix":"10.1038","volume":"15","author":[{"given":"Velavan","family":"Bakthavachalam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Sanborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manikannan","family":"Mathayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyajeet S.","family":"Salunkhe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason M.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Maienschein-Cline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Setty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basirudeen Syed Ahamed","family":"Kabeer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalees","family":"Rehman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bellur S.","family":"Prabhakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"22907_CR1","doi-asserted-by":"crossref","unstructured":"Miranda-Filho, A. et al. 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