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This study unveils a significant upregulation of nuclear receptor\u2010binding SET domain protein 2 (NSD2) in the intestines of obese humans and mice subjected to a high\u2010fat cholesterol diet (HFCD). Intestine\u2010specific NSD2 knockout attenuated the progression of intestinal barrier impairment and NASH, whereas NSD2 overexpression exacerbated this progression. Mechanistically, NSD2 directly regulates the transcriptional activation of <jats:italic>Ern1<\/jats:italic> by demethylating histone H3 at lysine 36 (H3K36me2), thus activating the ERN1\u2013JNK axis to intensify intestinal barrier impairment and subsequently foster NASH progression. These findings elucidate the crucial role of NSD2\u2010mediated H3K36me2 in intestinal barrier impairment, suggesting that targeting intestinal NSD2 can represent a novel therapeutic approach for NASH.<\/jats:p>","DOI":"10.1002\/advs.202402551","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T06:38:05Z","timestamp":1719383885000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Intestinal NSD2 Aggravates Nonalcoholic Steatohepatitis Through Histone Modifications"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4852-1423","authenticated-orcid":false,"given":"Yijia","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 P. R. 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