{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:50:12Z","timestamp":1782190212063,"version":"3.54.5"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012175","name":"Zhejiang Traditional Chinese Medicine Administration","doi-asserted-by":"publisher","award":["GZY-KJS-ZJ-115"],"award-info":[{"award-number":["GZY-KJS-ZJ-115"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Background<\/jats:title>\n \n Metabolic dysfunction-associated steatohepatitis (MASH) presents a growing global health challenge with limited therapeutic options. Rhein, an active anthraquinone derived from the traditional medicine rhubarb (\n Rheum palmatum L.<\/jats:italic>\n ), has demonstrated potential in alleviating metabolic liver disorders, yet its precise mechanism of action against MASH remains unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n An integrated strategy combining network pharmacology, molecular docking, and experimental validation was employed. A \u201cRhein-MASH\u201d target network was constructed to identify core targets. The\n in vivo<\/jats:italic>\n therapeutic effects and dose dependency of Rhein were assessed in a choline-deficient, high-fat diet (CDAHFD)-induced mouse MASH model.\n In vitro<\/jats:italic>\n mechanisms were investigated in PA\/OA-treated AML12 hepatocytes using functional assays, pharmacological inhibitors, and siRNA-mediated gene knockdown. Key signaling molecules and gene expression were analyzed via Western blot, qPCR, and immunohistochemistry.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Rhein treatment improved hepatic steatosis, inflammation, and liver injury in MASH mice in a dose-dependent manner without altering systemic lipid profiles. It selectively upregulated the expression of key genes involved in fatty acid \u03b2-oxidation (\n Acadl<\/jats:italic>\n ,\n Cpt1a<\/jats:italic>\n ) while suppressing pro-inflammatory cytokines (\n Tnf-\u03b1<\/jats:italic>\n ,\n Il-1\u03b2<\/jats:italic>\n ). Network pharmacology and molecular docking identified EGFR as a core target, with Rhein demonstrating potent binding affinity (docking score: \u22127.9\u00a0kcal\/mol).\n In vitro<\/jats:italic>\n experiments revealed that Rhein acts through EGFR to induces its autophosphorylation, and sequentially activates the downstream PI3K\/AKT signaling pathway. This signaling module coordinately enhances fatty acid oxidation\u2013related gene expression and reduces inflammatory gene expression partly through PPAR\u03b1, thereby effectively ameliorating lipid accumulation and inflammatory phenotypes in hepatocytes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n This study elucidates that Rhein ameliorates MASH by activating the EGFR\/PI3K\/AKT\/PPAR\u03b1 pathway, which coordinately enhances hepatic fatty acid oxidation and suppresses inflammation. These findings position Rhein as a multi-target regulator and suggest the EGFR-PPAR\u03b1 axis is a promising therapeutic target for MASH.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2026.1844294","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:31:03Z","timestamp":1782189063000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rhein ameliorates MASH via EGFR\/AKT\/PPAR\u03b1-mediated coordinated regulation of metabolism and inflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Liyan","family":"Song","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First People\u2019s Hospital of Linping District","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, The First People\u2019s Hospital of Linping District","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Sui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"173908","DOI":"10.1016\/j.ejphar.2021.173908","article-title":"A research update on the therapeutic potential of rhein and its derivatives","volume":"899","author":"Cheng","year":"2021","journal-title":"Eur. 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