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Nevertheless, the dynamic alterations and functions of histone Kcr in inflammatory bowel disease (IBD) remain poorly explored. Herein, a notable decrease of both Pan\u2010Kcr and ACSS2 (acyl\u2010CoA synthetase short\u2010chain family member 2), the key enzyme for crotonyl\u2010CoA generation, is revealed in inflamed intestinal epithelial cells. Genetic or pharmacological inhibition of ACSS2 dramatically impairs mouse intestinal barrier integrity and exacerbates colitis. Mechanistically, ACSS2\u2010mediated histone H4 lysine 12 crotonylation (H4K12cr) upregulates CLDN7 expression to fortify intestinal epithelial barrier, which can be augmented by crotonate supplementation. Furthermore, tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) is revealed to enhance the m6A modification of\n                    <jats:italic>ACSS2<\/jats:italic>\n                    mRNA, consequently destabilizing and downregulating\n                    <jats:italic>ACSS2<\/jats:italic>\n                    . Combinational therapy involving anti\u2010TNF\u2010\u03b1 and crotonate can significantly ameliorate colitis. Overall, ACSS2\u2010mediated H4K12cr emerges as a pivotal modulator governing intestinal barrier function during IBD progression.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500461","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T14:29:08Z","timestamp":1752330548000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["ACSS2\u2010Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2935-3320","authenticated-orcid":false,"given":"Ming","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong 510655 China"},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth 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