{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T15:21:41Z","timestamp":1781191301050,"version":"3.54.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease posing a severe threat to human health, currently lacks specific therapeutic drugs. Our previous studies have demonstrated that <jats:italic>Polygala tenuifolia<\/jats:italic> Willd. Extract (EPT) can significantly suppress the PGE2 inflammatory pathway, thereby exerting anti-inflammatory and antioxidant effects, as well as improving lipid metabolism. These findings suggest that EPT might hold potential value for the prevention and treatment of NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>This study aims to investigate the role of EPT in NAFLD and its multi - target synergistic mechanisms, and to preliminarily explore its impact on the early progression of NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The detection of EPT components in rat blood was performed by UPLC-MS\/MS. A rat NAFLD model was established using a high-fat emulsion gavage method, and pathological changes in liver tissue were assessed via H&amp;amp;E, Oil Red O, and Sirius Red staining. RNA-seq, immunohistochemistry, RT-qPCR, and Western blotting were used to evaluate the expression of cyclooxygenase 1 (COX1), cyclooxygenase 2 (COX2), inflammatory factors (IL-1, IL-6, TNF-\u03b1), oxidative stress-related proteins in the KEAP1 pathway, proteins involved in the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, and apoptosis-related proteins (Bcl-2 and Caspase-3).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>EPT significantly attenuated the histopathological alterations in liver tissue and ameliorated lipid accumulation in the livers of NAFLD rats. RNA-seq identified differential changes in the arachidonic acid metabolism, inflammatory, and endoplasmic reticulum-related pathways. Immunohistochemistry showed that EPT reversed the elevated expression of COX2, the ER stress marker GRP78, and PERK in the liver tissue of model rats. RT-qPCR and Western blot analyses confirmed that EPT reduced the expression of COX1, COX2, IL-1\u03b2, IL-6, TNF-\u03b1, and KEAP1, while increasing Nrf2 and HO-1 levels. Furthermore, EPT downregulated GRP78, PERK, p-PERK, eIF2\u03b1, p-eIF2\u03b1, ATF4, CHOP, Bcl-2, and Caspase-3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results suggest that EPT might exert anti - inflammatory and antioxidant effects by modulating the COX2 pathway in NAFLD rats, downregulate the ER stress PERK - eIF2\u03b1 - ATF4 signaling pathway, alleviate ER stress, inhibit apoptosis, and delay NAFLD progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1595752","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T05:21:08Z","timestamp":1749705668000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Polygala tenuifolia Willd. Extract delays non-alcoholic fatty liver disease progression in rats via the COX2 and PERK-elF2\u03b1-ATF4 pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhiliang","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongshi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kezheng","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanju","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3390\/antiox10020174","article-title":"Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy","volume":"10","author":"Arroyave-Ospina","year":"2021","journal-title":"Antioxidants"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.mad.2016.07.001","article-title":"Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis","volume":"157","author":"Bozaykut","year":"2016","journal-title":"Mech. 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