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ATP citrate lyase (ACLY), a rate\u2010limiting enzyme of de novo lipid synthesis, plays an important role in tumor progression and chemotherapy. Here, It is demonstrated that deacetylation of ACLY is critical for chemoresistance in CRC. Through proteomic screening acetylated proteins in chemoresistant patient\u2010derived cells, It is identified that ACLY is deacetylated at K978 site, which induces the relocation of ACLY to the nucleus and promotes its binding to RNA\u2010binding protein 15 (RBM15). This facilitates N\n                    <jats:sup>6<\/jats:sup>\n                    \u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) methylation of NOXA (also known as PMAIP1, phorbol\u201012\u2010myristate\u201013\u2010acetate\u2010induced protein 1) and decreases the stability of NOXA mRNA, resulting in chemoresistance. With the selective inhibitor Santacruzamate A, targeting the deacetylase histone deacetylase 2 (HDAC2) to inhibit the acetylation may enhance the sensitivity of chemoresistance. These findings provide new insights into the mechanism of ACLY deacetylation promoting chemoresistance and suggest a potential therapeutic strategy to mitigate the chemoresistant effects.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503323","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T02:57:11Z","timestamp":1759460231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Deacetylation of ACLY Mediates RNA M\n                    <sup>6<\/sup>\n                    A\u2010Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-0146","authenticated-orcid":false,"given":"Jun","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine Shanghai Jiao Tong University 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