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DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of\n                    <jats:italic>n<\/jats:italic>\n                    \u2010butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study,\n                    <jats:italic>NR4A1<\/jats:italic>\n                    mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA\u2010seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that\n                    <jats:italic>NR4A1<\/jats:italic>\n                    mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of\n                    <jats:italic>COL1A1<\/jats:italic>\n                    expression, which was upregulated by TGF\u2010\u03b2. BP also ameliorated gingival overgrowth in DIGE mice and reduced\n                    <jats:italic>Col1a1<\/jats:italic>\n                    and\n                    <jats:italic>Pai1<\/jats:italic>\n                    expression. BP also decreased\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    mRNA expression in gingival tissue in DIGE. RNA\u2010seq results showed an increase in the expression of several genes related to mitogen\u2010activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP\u2010induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE.\n                  <\/jats:p>","DOI":"10.1002\/biof.2077","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T09:18:29Z","timestamp":1729761509000},"page":"1192-1207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>Nuclear receptor 4A1 (NR4A1)<\/scp>\n                    upregulated by\n                    <i>n<\/i>\n                    \u2010butylidenephthalide via the mitogen\u2010activated protein kinase (\n                    <scp>MAPK)<\/scp>\n                    pathway ameliorates drug\u2010induced gingival enlargement"],"prefix":"10.1002","volume":"50","author":[{"given":"Tomoya","family":"Ueda","sequence":"first","affiliation":[{"name":"Department of Periodontal Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4281-3216","authenticated-orcid":false,"given":"Shinji","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurika","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuminori","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima 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