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Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Coptidis rhizoma<\/jats:italic>, a botanical drug derived from the dried rhizome of Coptis species (e.g., <jats:italic>Coptis chinensis<\/jats:italic>), is characterized by abundant natural sources, significant bioactivity, and high safety. It holds considerable potential for translational applications in metabolic diseases, particularly in ameliorating type 2 diabetes mellitus (T2DM)-related metabolic dysfunction-associated steatohepatitis (MASH). However, mechanistic studies on <jats:italic>Coptidis rhizoma<\/jats:italic> remain limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>This study aimed to evaluate the therapeutic effects of <jats:italic>Coptidis rhizoma<\/jats:italic> on hepatic histological and functional damage, metabolic disorders, and insulin resistance in T2DM-related MASH and investigate its underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two-day-old male C57BL\/6J mice were subcutaneously injected with streptozotocin (200\u00a0\u03bcg\/20\u00a0\u03bcL per mouse). At 4\u00a0weeks of age, the mice were weaned and switched to a high-fat diet until week 9 to induce T2DM-related MASH. Starting from week 5, <jats:italic>Coptidis rhizoma<\/jats:italic> decoction was administered via oral gavage for four consecutive weeks to conduct <jats:italic>in vivo<\/jats:italic> studies. Additionally, hepatocytes were isolated from the model mice and exposed <jats:italic>in vitro<\/jats:italic> to epiberberine, the active metabolite of <jats:italic>Coptidis rhizoma<\/jats:italic>, for cellular-level investigations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Coptidis rhizoma<\/jats:italic> significantly attenuated hepatic inflammatory lesions, reduced the non-alcoholic fatty liver disease activity score, improved liver function, and alleviated glucose and lipid metabolism disorders and insulin resistance in a dose-dependent manner in T2DM-related MASH mice. At the transcriptional level, key components of the interleukin-17 receptor A (IL-17RA)\/nuclear factor kappa B (NF-\u03baB) signaling pathway were upregulated in the hepatocytes of T2DM-related MASH mice, and both <jats:italic>Coptidis rhizoma<\/jats:italic> and epiberberine downregulated their expressions. Furthermore, <jats:italic>Coptidis rhizoma<\/jats:italic> and epiberberine suppressed the secretion of pro-inflammatory cytokines associated with the IL-17RA\/NF-\u03baB pathway in hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Coptidis rhizoma<\/jats:italic> ameliorates pathological phenotypes in T2DM-related MASH by inhibiting the IL-17RA\/NF-\u03baB signaling pathway, and its active metabolite epiberberine is involved in mediating these protective effects.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1667937","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:25:30Z","timestamp":1759123530000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Coptidis rhizoma ameliorates type 2 diabetes mellitus-related metabolic dysfunction-associated steatohepatitis by downregulating the IL-17RA\/NF-\u03baB signaling pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Ning","family":"Yao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxin","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajuan","family":"Geng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.biopha.2018.02.103","article-title":"The potential pathogenic role of IL-17\/Th17 cells in both type 1 and type 2 diabetes mellitus","volume":"101","author":"Abdel-Moneim","year":"2018","journal-title":"Biomed. 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