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Notably, the activation of Nrf2 is regarded as an effective strategy for controlling oxidation. The novel 2,3\u2010dihydroflavonoid compound farrerol, which is extracted from <jats:italic>Rhododendron<\/jats:italic>, possesses antioxidant properties. In this study, we investigated the mechanism by which farrerol protects against oxidative damage mediated by hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) in adult retinal pigment epithelial cell line 19 (ARPE\u201019) cells. Farrerol supplementation conspicuously reversed H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010related cell damage through declining the generation of intracellular reactive oxygen species (ROS) and MDA and increasing the concentrations of GSH and SOD. According to the results of the apoptosis assay, a farrerol pretreatment decreased the protein expression of the Bax\/Bcl\u20102, cleaved caspase\u20103, PARP, caspase\u20108, and caspase\u20109 proteins. Furthermore, farrerol markedly activated Nrf2, thereby increasing the levels of antioxidant enzymes downstream of Nrf2, such as HO\u20101, NQO1, and GCLM. Knockdown of Nrf2 with a specific siRNA successfully suppressed farrerol\u2010mediated HO\u20101 transcription and partially abolished the cytoprotective effect on ARPE\u201019 cells. Meanwhile, farrerol induced Akt and MAPK phosphorylation in a dose\u2010related way. However, inhibiting Akt and MAPK substantially blocked the cytoprotective functions of farrerol. Therefore, farrerol enhanced Nrf2\u2010mediated cytoprotection of oxidative damage caused by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>, which may be inseparable from the activation of Akt and MAPK.<\/jats:p>","DOI":"10.1155\/2021\/8847844","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T05:50:06Z","timestamp":1614923406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Farrerol Enhances Nrf2\u2010Mediated Defense Mechanisms against Hydrogen Peroxide\u2010Induced Oxidative Damage in Human Retinal Pigment Epithelial Cells by Activating Akt and 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