{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T18:43:47Z","timestamp":1786214627312,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,4,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Gentiopicroside (GPS), derived from Gentiana manshurica, exhibits multiple pharmacological activities, such as anti\u2010inflammatory and antioxidant effects, but its role and mechanisms in treating type 2 diabetes mellitus (T2DM) remain unclear. This study explored GPS's therapeutic effects and underlying mechanisms in\u00a0vitro and in\u00a0vivo. In a T2DM mouse model induced by a high\u2010fat diet (HFD) and streptozotocin (STZ), the results demonstrated that GPS significantly relieved diabetic symptoms, corrected oral glucose tolerance impairment, enhanced insulin sensitivity, and ameliorated lipid metabolism disorders. GPS also increased the activities of antioxidant enzymes, elevated the levels of antioxidant substances, reduced malondialdehyde (MDA) in serum and liver, and ameliorated hepatic insulin resistance (IR). In palmitic acid (PA)\u2010induced HepG2 cells, GPS dramatically inhibited PA\u2010induced cytotoxicity and oxidative stress by increasing glutathione (GSH) levels and superoxide dismutase (SOD) activities while lowering malondialdehyde (MDA) levels, and reversed PA\u2010induced IR. Mechanistically, GPS regulated protein expression in the PI3K\/AKT\/Nrf2 pathway and promoted Nrf2 nuclear translocation in both models. More importantly, further studies revealed that LY294002 (a PI3K inhibitor) or ML385 (an Nrf2 inhibitor) suppressed the protective effects of GPS against PA\u2010induced hepatic oxidative damage. In conclusion, GPS alleviates hepatic oxidative damage, IR and delays the progression of T2DM through activating the PI3K\/AKT\/Nrf2 signaling pathway, providing an important foundation for further development and utilization of GPS. However, this study still has limitations including the lack of a positive control drug and insufficient exploration of the relevant molecular mechanisms, and will further improve the research and explore the clinical potential of GPS in the future.<\/jats:p>","DOI":"10.1096\/fj.202600873r","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T11:43:58Z","timestamp":1776858238000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gentiopicroside Alleviates Type 2 Diabetes Mellitus by Ameliorating Hepatic Oxidative Stress via Activation of the\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/Nrf2 Signaling Pathway"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6736-2167","authenticated-orcid":false,"given":"Xing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Long","sequence":"additional","affiliation":[{"name":"Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry Nanchong Vocational and Technical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qitong","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingcan","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy North Sichuan Medical College  Nanchong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Minhang Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2022.115196"},{"key":"e_1_2_12_3_1","article-title":"Global Type 1 Diabetes Prevalence, Incidence, and Mortality Estimates 2025: Results From the International Diabetes Federation Atlas, 11th Edition, and the T1D Index Version 3.0, Diabetes Res","volume":"225","author":"Ogle G. 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