{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:10:54Z","timestamp":1786122654312,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease with limited pharmacological treatment options. Wogonoside (WOG), a flavonoid isolated from Scutellaria baicalensis, exhibits anti-inflammatory, antioxidant, and lipid-lowering activities; however, its effects and underlying mechanisms in MASH remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A high-fat and high-fructose diet (HFFD)-induced mouse model of MASH and free fatty acid (FFA)-induced HepG2 cell steatosis model were used to evaluate the hepatoprotective effects of WOG. Liver histopathology, serum biochemical parameters, glucose tolerance, lipid accumulation, oxidative stress, ferroptosis-associated indicators, transcriptomic profiling, and expression of relevant proteins were assessed. The anti-ferroptotic effects of WOG were further examined using erastin and ferrostatin-1 in HepG2 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WOG administration ameliorated HFFD-induced obesity, hepatic steatosis, hepatocellular ballooning, liver injury, dyslipidemia, insulin resistance, oxidative stress, and inflammatory responses in mice. Transcriptomic analysis indicated that WOG-responsive genes were enriched in lipid metabolism, peroxisome proliferator-activated receptor signaling, AMPK signaling, and ferroptosis-related pathways. In liver tissues and FFA-treated HepG2 cells, WOG increased AMPK phosphorylation and upregulated the expression of PGC-1\u03b1, PPAR\u03b1, and CPT-1, while reducing the expression of SREBP-1c and its downstream lipogenic proteins, including ACLY, ACACA, FASN, and SCD-1. These changes were accompanied by decreased hepatic and intracellular triglyceride accumulation. In addition, WOG reduced reactive oxygen species, restored mitochondrial membrane potential, increased Nrf2 and HO-1 expression, and attenuated inflammatory responses. WOG also decreased Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation and lipid peroxidation, restored glutathione homeostasis, and increased xCT and GPX4 expression in vivo and in vitro. Moreover, WOG counteracted erastin-induced ferroptosis-related changes and exhibited effects similar to those of ferrostatin-1 in FFA-treated HepG2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>WOG alleviates experimental MASH by improving hepatic lipid metabolic homeostasis and suppressing ferroptosis-associated injury. These protective effects are associated with activation of AMPK signaling and restoration of the xCT\/GPX4 antioxidant defense axis. WOG may therefore represent a promising candidate for the pharmacological management of MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1852232","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:09:06Z","timestamp":1786100946000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Wogonoside alleviates metabolic dysfunction-associated steatohepatitis by modulating AMPK and xCT\/GPX4 pathways to restrain lipid dysregulation and ferroptosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Daoping","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Natural Products Research Center of Guizhou Province, Guizhou Medical University","place":["Guiyang, China"]},{"name":"School of Pharmaceutical Sciences, Guizhou Medical 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