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However, the upstream mechanisms driving MEN1 silencing remain unclear. Here, a pooled epigenetic CRISPR\u2013Cas9 screen identified the NAD\n                    <jats:sup>+<\/jats:sup>\n                    \u2010dependent deacetylase SIRT7 as a critical suppressor of MEN1 expression. Mechanistically, SIRT7 interacts with DNMT1 and promotes catalytic activity\u2010dependent recruitment of DNMT1 to the MEN1 promoter, leading to promoter hypermethylation and transcriptional repression. Clinically, SIRT7 is overexpressed in PanNET tissues and inversely correlates with MEN1 levels and patient prognosis. Genetic or pharmacologic inhibition of SIRT7 restored MEN1 expression, reduced MRN complex abundance, and impaired double\u2010strand break repair. Graded MEN1 re\u2010expression demonstrated a quantitative relationship between MRN levels, DNA repair efficiency, and radiosensitivity. Functionally, SIRT7 inhibition enhanced radiation\u2010induced DNA damage and apoptosis in a partially MEN1\u2010dependent manner and significantly suppressed tumor growth in patient\u2010derived organoids and multiple independent xenograft models. Collectively, these findings define a catalytic activity\u2010dependent SIRT7\u2013DNMT1\u2013MEN1 epigenetic axis that modulates DDR and radiosensitivity, supporting SIRT7 targeting as a strategy to improve radiotherapy efficacy in PanNETs.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519824","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T11:53:32Z","timestamp":1776081212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of SIRT7 Overcomes Radioresistance in Pancreatic Neuroendocrine Tumors by Reactivating MEN1 Expression"],"prefix":"10.1002","volume":"13","author":[{"given":"Jianyun","family":"Jiang","sequence":"first","affiliation":[{"name":"Center For Neuroendocrine Tumors Fudan University Shanghai Cancer Center  Shanghai China"},{"name":"Department of Oncology, Shanghai Medical College Fudan University  Shanghai 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