{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:58:44Z","timestamp":1776675524005,"version":"3.51.2"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":109,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by elevated blood glucose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study is aimed at evaluating the efficacy of 4\u2010methylesculetin in mitigating insulin resistance (IR) in HepG2 cells, thereby identifying the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An HepG2 cell insulin resistance (IR\u2010HepG2) model was established using high glucose and high insulin. Cell viability was evaluated via the CCK\u20108 test to ascertain the safety dosage, whereas the impact of 4\u2010methylesculetin on glucose metabolism was investigated by quantifying glucose uptake and glycogen levels. The impact of 4\u2010methylesculetin on oxidative stress within the IR\u2010HepG2 model was assessed through the analysis of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH\u2010PX). To investigate the underlying mechanisms, Western blot analysis was performed to determine the protein expression levels of key molecules involved in insulin signaling and oxidative stress, including p\u2010AMPK, AMPK, SIRT1, NOX4, p\u2010AKT, AKT, p\u2010GSK3\n                      <jats:italic>\u03b2<\/jats:italic>\n                      , GSK3\n                      <jats:italic>\u03b2<\/jats:italic>\n                      , p\u2010FOXO1, FOXO1, p\u2010GYS1, GYS1, PEPCK, GLUT2, and G6Pase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the IR\u2010HepG2 model, 4\u2010methylesculetin treatment significantly enhanced glucose consumption and glycogen synthesis (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.01). It also markedly alleviated oxidative stress by increasing the activities of antioxidant enzymes SOD and GSH\u2010PX (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05 or\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.01), and reducing the levels of ROS and MDA (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.01). Western blot analysis revealed that these beneficial effects were mediated through the activation of the AMPK\/FOXO1 and PI3K\/AKT\/GSK3\n                      <jats:italic>\u03b2<\/jats:italic>\n                      pathways, as well as the activation of SIRT1, which led to the suppression of NOX4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      4\u2010Methylesculetin may ameliorate IR in HepG2 cells by improving glucose metabolism via AMPK\/FOXO1 and PI3K\/AKT\/GSK3\n                      <jats:italic>\u03b2<\/jats:italic>\n                      pathways and attenuating oxidative stress via SIRT1\/NOX4 axis. In addition, 4\u2010methylesculetin has the potential to be a therapeutic agent for T2DM.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/jdr\/8023146","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:27:36Z","timestamp":1776673656000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u2010Methylesculetin Ameliorates Hepatic Insulin Resistance in HepG2 Cells Through AMPK\/FOXO1, PI3K\/AKT\/GSK3\n                    <i>\u03b2<\/i>\n                    Pathways and SIRT1\/NOX4 Axis"],"prefix":"10.1155","volume":"2026","author":[{"given":"Xiaohua","family":"Su","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhang","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yige","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiamei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Shan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-6814","authenticated-orcid":false,"given":"Menglu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanxin","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anfeng","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4795-7219","authenticated-orcid":false,"given":"Yongcheng","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3093-1343","authenticated-orcid":false,"given":"Baosheng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_2_14_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2025.110521"},{"key":"e_1_2_14_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2025.118264"},{"key":"e_1_2_14_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-022-01453-4"},{"key":"e_1_2_14_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112563"},{"key":"e_1_2_14_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2025.108614"},{"key":"e_1_2_14_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.7"},{"key":"e_1_2_14_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.11.018"},{"key":"e_1_2_14_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.26097"},{"key":"e_1_2_14_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MR0220-243R"},{"key":"e_1_2_14_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.12.026"},{"key":"e_1_2_14_11_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.009"},{"key":"e_1_2_14_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/jf2036559"},{"key":"e_1_2_14_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5392"},{"key":"e_1_2_14_14_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1265219"},{"key":"e_1_2_14_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00553.2018"},{"key":"e_1_2_14_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.8381"},{"key":"e_1_2_14_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114675"},{"key":"e_1_2_14_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12774"},{"key":"e_1_2_14_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/jf403840c"},{"key":"e_1_2_14_20_2","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S1734-1140(13)71016-8","article-title":"Effects of Sesquiterpene, Flavonoid and Coumarin Types of Compounds From Artemisia Annua L. on Production of Mediators of Angiogenesis","volume":"65","author":"Zhu X. 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