{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:00:04Z","timestamp":1785218404785,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"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. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to investigate the effects of stigmasterol on obesity-related insulin resistance and to explore the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Network pharmacology was used to screen the active components and key targets of Angelica sinensis that act on obesity and insulin resistance, and molecular docking was performed to assess the binding potential between stigmasterol and PPAR\u03b3. In cell experiments, an insulin-resistant 3T3-L1 adipocyte model was treated with different concentrations of stigmasterol and rosiglitazone. Lipid accumulation, oxidative stress indicators, and protein expression of the PPAR\u03b3 pathway were measured. In animal experiments, high-fat diet-induced obese mice were administered stigmasterol and rosiglitazone, and serum metabolic parameters, histopathological changes, and hepatic oxidative stress and PPAR\u03b3 pathway protein expression were measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Network pharmacology identified 90 overlapping targets, with PPAR\u03b3 occupying a central position in the core network. Molecular docking indicated that stigmasterol showed good binding affinity for PPAR\u03b3. In insulin-resistant 3T3-L1 adipocytes, stigmasterol reduced intracellular TG and TC contents and lipid droplet accumulation, decreased ROS and MDA levels, increased the activities of CAT, GPx, and SOD, and upregulated the protein expression of PPAR\u03b3, the p-Akt\/Akt ratio, and GLUT4 (p &amp;lt; 0.05). In obese mice, stigmasterol decreased the serum levels of fasting insulin, fasting blood glucose, HOMA-IR, TG, and TC, increased HOMA-ISI, reduced adipocyte size, alleviated hepatic steatosis, and lowered serum ALT and AST levels. Meanwhile, stigmasterol reduced hepatic ROS and MDA levels, restored antioxidant enzyme activities, and upregulated the protein expression of PPAR\u03b3, p-Akt\/Akt, and GLUT4 in the liver (p &amp;lt; 0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Stigmasterol improved obesity-related glycolipid metabolic disorder and insulin resistance both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and its mechanism involved activation of the PPAR\u03b3 pathway and attenuation of oxidative stress.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1888104","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:34:14Z","timestamp":1785216854000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stigmasterol ameliorates obesity-associated insulin resistance by activating the PPAR\u03b3 pathway and alleviating oxidative stress"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanan","family":"Zhao","sequence":"first","affiliation":[{"name":"Qilu Medical University","place":["Zibo, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Yantaishan Hospital","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cmet.2021.12.012","article-title":"Why does obesity cause diabetes","volume":"34","author":"Klein","year":"2022","journal-title":"Cell Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1499565","article-title":"Associated factors and principal pathophysiological mechanisms of type 2 diabetes mellitus","volume":"16","author":"Wang","year":"2025","journal-title":"Front Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.66570","article-title":"Biomarkers of oxidative stress and their clinical relevance in type 2 diabetes mellitus patients: a systematic review","volume":"16","author":"S.","year":"2024","journal-title":"Cureus"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1634982","article-title":"The efficacy of saffron supplementation on inflammation and oxidative stress in patients with type-2 diabetes mellitus: a meta-analysis","volume":"16","author":"Qin","year":"2025","journal-title":"Front Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/35013000","article-title":"Roles of PPARs in health and disease","volume":"405","author":"Kersten","year":"2000","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.47.4.507","article-title":"PPAR-gamma: adipogenic regulator and thiazolidinedione receptor","volume":"47","author":"Spiegelman","year":"1998","journal-title":"Diabetes"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ph16040535","article-title":"Insulin sensitization by PPAR\u03b3 and GLUT-4 overexpression\/translocation mediates the antidiabetic effect of Plantago australis","volume":"16","author":"Estrada-Soto","year":"2023","journal-title":"Pharm (Basel Switzerland)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102848","article-title":"Protective effects of luteolin against amyloid beta-induced oxidative stress and mitochondrial impairments through peroxisome proliferator-activated receptor \u03b3-dependent mechanism in Alzheimer's disease","volume":"66","author":"He","year":"2023","journal-title":"Redox Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.freeradbiomed.2024.10.001","article-title":"Isoliquiritigenin mitigates intervertebral disc degeneration induced by oxidative stress and mitochondrial impairment through a PPAR\u03b3-dependent pathway","volume":"225","author":"Huang","year":"2024","journal-title":"Free Radical Biol Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s44321-025-00216-4","article-title":"Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity","volume":"17","author":"Chang","year":"2025","journal-title":"EMBO Mol Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/6280972","article-title":"Angelica sinensis suppresses body weight gain and alters expression of the FTO gene in high-fat-diet induced obese mice","volume":"2017","author":"Zhong","year":"2017","journal-title":"BioMed Res Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.874914","article-title":"Polycystic ovary syndrome: a disorder of reproductive age, its pathogenesis, and a discussion on the emerging role of herbal remedies","volume":"13","author":"Zeng","year":"2022","journal-title":"Front Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153415","article-title":"The potential LXR\u03b2 agonist stigmasterol protects against hypoxia\/reoxygenation injury by modulating mitophagy in primary hippocampal neurons","volume":"81","author":"Haque","year":"2021","journal-title":"Phytomedicine: Int J Phytotherapy Phytopharmacology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11101912","article-title":"Health benefits and pharmacological properties of stigmasterol","volume":"11","author":"Bakrim","year":"2022","journal-title":"Antioxidants (Basel Switzerland)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.741934","article-title":"Stigmasterol restores the balance of Treg\/Th17 cells by activating the butyrate-PPAR\u03b3 axis in colitis","volume":"12","author":"Wen","year":"2021","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2024.13351","article-title":"Stigmasterol exerts antiglioma effects by regulating lipid metabolism","volume":"30","author":"Wei","year":"2024","journal-title":"Mol Med Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28073001","article-title":"The SWGEDWGEIW from soybean peptides reduces insulin resistance in 3T3-L1 adipocytes by activating p-Akt\/GLUT4 signaling pathway","volume":"28","author":"Yi","year":"2023","journal-title":"Molecules (Basel Switzerland)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.723623","article-title":"DMRT2 interacts with FXR and improves insulin resistance in adipocytes and a mouse model","volume":"12","author":"Tao","year":"2021","journal-title":"Front Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2025.110147","article-title":"Stigmasterol mitigates cholesterol gallstone formation by modulating bile acid metabolism and gut microbiota in mice fed a lithogenic diet","volume":"148","author":"Deng","year":"2026","journal-title":"J Nutr Biochem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjnut.2023.05.026","article-title":"Stigmasterol protects against steatohepatitis induced by high-fat and high-cholesterol diet in mice by enhancing the alternative bile acid synthesis pathway","volume":"153","author":"Xin","year":"2023","journal-title":"J Nutr"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2022.100305","article-title":"Rosiglitazone reverses inflammation in epididymal white adipose tissue in hormone-sensitive lipase-knockout mice","volume":"64","author":"Kotzbeck","year":"2023","journal-title":"J Lipid Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2899","article-title":"MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity","volume":"18","author":"Kusminski","year":"2012","journal-title":"Nat Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2024.111157","article-title":"Jujuboside A through YY1\/CYP2E1 signaling alleviated type 2 diabetes-associated fatty liver disease by ameliorating hepatic lipid accumulation, inflammation, and oxidative stress","volume":"400","author":"Zhang","year":"2024","journal-title":"Chem Biol Interact"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01638","article-title":"The impact of oxidative stress on adipose tissue energy balance","volume":"10","author":"Masschelin","year":"2019","journal-title":"Front Physiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2019.06.005","article-title":"Oleic acid and eicosapentaenoic acid reverse palmitic acid-induced insulin resistance in human HepG2 cells via the reactive oxygen species\/JUN pathway","volume":"19","author":"Sun","year":"2021","journal-title":"Genomics Proteomics Bioinf"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/toxres\/tfad055","article-title":"HM-chromanone isolated from Portulaca oleracea L. alleviates insulin resistance and inhibits gluconeogenesis by regulating palmitate-induced activation of ROS\/JNK in HepG2 cells","volume":"12","author":"Park","year":"2023","journal-title":"Toxicol Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1769545","article-title":"Endoplasmic reticulum stress in skeletal muscle dysfunction of type 2 diabetes: mechanisms and therapeutic implications","volume":"17","author":"Wang","year":"2026","journal-title":"Front Endocrinol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1569866","article-title":"Zinc sulfate improves insulin resistance, oxidative stress and apoptosis in liver tissues of PCOS rats through the NF-\u03baB pathway","volume":"16","author":"Kang","year":"2025","journal-title":"Front Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-025-07502-2","article-title":"Stigmasterol exerts antioxidant effects through activation of the Keap1\/Nrf2 signaling pathway in Parkinson's disease model","volume":"24","author":"Tong","year":"2025","journal-title":"J Transl Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.155116","article-title":"Astragaloside IV inhibits AOM\/DSS-induced colitis-associated tumorigenesis via activation of PPAR\u03b3 signaling in mice","volume":"121","author":"Liang","year":"2023","journal-title":"Phytomedicine: Int J Phytotherapy Phytopharmacology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.brainresbull.2021.11.001","article-title":"Silent information regulator 1 ameliorates oxidative stress injury via PGC-1\u03b1\/PPAR\u03b3-Nrf2 pathway after ischemic stroke in rat","volume":"178","author":"Zhou","year":"2022","journal-title":"Brain Res Bull"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.157003","article-title":"Selective PPAR\u03b3 modulator alpinetin restores insulin sensitivity and protects from bone loss in type 2 diabetes","volume":"145","author":"Zhao","year":"2025","journal-title":"Phytomedicine: Int J Phytotherapy Phytopharmacology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s10020-024-00889-6","article-title":"RNA-binding protein GIGYF2 orchestrates hepatic insulin resistance through STAU1\/PTEN-mediated disruption of the PI3K\/AKT signaling cascade","volume":"30","author":"Lv","year":"2024","journal-title":"Mol Med (Cambridge Mass)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2022.154204","article-title":"Kutkin, iridoid glycosides enriched fraction of Picrorrhiza kurroa promotes insulin sensitivity and enhances glucose uptake by activating PI3K\/Akt signaling in 3T3-L1 adipocytes","volume":"103","author":"Sinha","year":"2022","journal-title":"Phytomedicine: Int J Phytotherapy Phytopharmacology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/nu17152456","article-title":"Flavone C-glycosides from Dianthus superbus L. attenuate metabolic dysfunction-associated steatotic liver disease (MASLD) via multi-pathway regulations","volume":"17","author":"Chu","year":"2025","journal-title":"Nutrients"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1888104\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:34:15Z","timestamp":1785216855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1888104\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":35,"alternative-id":["10.3389\/fendo.2026.1888104"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1888104","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"article-number":"1888104"}}