biostudies-literatureYuan MShenzhen Medical Research FundJiangxi Provincial Natural Science FoundationNational Key R&D Program of ChinaXinjiang Uyghur Autonomous Regional Natural Science FoundationNational Natural Science Foundation of Chinathe Starting Funding of Faculty from Sun Yat-sen UniversityGuangzhou Basic and Applied Basic Research Foundationthe "Jie Bang Gua Shuai" Program from The Sixth Affiliated Hospital, Sun Yat-sen UniversityFundamental Research Funds for the Central Universities, Sun Yat-sen UniversityXinjiang Uyghur Autonomous Regional Collaborative Innovation Special Project-Science and Technology Assistance to XinjiangKey Research and Development Program of Guangzhouthe National Key Clinical DisciplineGuangdong Basic and Applied Basic Research Foundationthe program of Guangdong Provincial Clinical Research Center for Digestive Diseasese00461https://www.ebi.ac.uk/biostudies/studies/S-EPMC12376547biostudies-literatureUnknown12(30)Histone lysine crotonylation (Kcr), a highly conserved posttranslational modification, plays critical roles in various biological processes. Nevertheless, the dynamic alterations and functions of histone Kcr in inflammatory bowel disease (IBD) remain poorly explored. Herein, a notable decrease of both Pan-Kcr and ACSS2 (acyl-CoA synthetase short-chain family member 2), the key enzyme for crotonyl-CoA 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-mediated 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-α (TNF-α) is revealed to enhance the m6A modification of ACSS2 mRNA, consequently destabilizing and downregulating ACSS2. Combinational therapy involving anti-TNF-α and crotonate can significantly ameliorate colitis. Overall, ACSS2-mediated H4K12cr emerges as a pivotal modulator governing intestinal barrier function during IBD progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany)ACSS2-Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7.PMC123765472023A04J182020212762024E020632022A1515111043824705702020B11111700042022JBGS012024A151501281320242BAB255372024D01C052022YFA1304000A240200223xkjc0232024B03J0211823706752024A151501307223qnpy14782303928Ke HHu TYu RChao KHuang JLi QYuan MLin ZLiang GLan PYe SGao XChen SZhang CWu XfalseACSS2-Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7.Histone lysine crotonylation (Kcr), a highly conserved posttranslational modification, plays critical roles in various biological processes. Nevertheless, the dynamic alterations and functions of histone Kcr in inflammatory bowel disease (IBD) remain poorly explored. Herein, a notable decrease of both Pan-Kcr and ACSS2 (acyl-CoA synthetase short-chain family member 2), the key enzyme for crotonyl-CoA 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-mediated 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-α (TNF-α) is revealed to enhance the m6A modification of ACSS2 mRNA, consequently destabilizing and downregulating ACSS2. Combinational therapy involving anti-TNF-α and crotonate can significantly ameliorate colitis. Overall, ACSS2-mediated H4K12cr emerges as a pivotal modulator governing intestinal barrier function during IBD progression.2025-01-01T00:00:00Z2025 Aug2026-05-09T17:49:05.982Z2026-04-08T01:08:22.824ZS-EPMC123765474065065810.1002/advs.202500461