{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:24:50Z","timestamp":1777947890366,"version":"3.51.4"},"reference-count":62,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["21806114"],"award-info":[{"award-number":["21806114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Xinjiang Production and Construction Corps Guiding Science and Technology Plan","award":["2022ZD047"],"award-info":[{"award-number":["2022ZD047"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2\u2032,4,4\u2032-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2\/antioxidant response element (Nrf2\/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2\/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2\/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2\/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages.<\/jats:p>","DOI":"10.3390\/biom16050674","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:54:07Z","timestamp":1777654447000},"page":"674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the Nrf2\/ARE Pathway Attenuates BDE-47-Induced Immunotoxicity in RAW264.7 Macrophages"],"prefix":"10.3390","volume":"16","author":[{"given":"Qian","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resources and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832000, China"},{"name":"Department of Pharmacology, School of Pharmacy, Shihezi University, Shihezi 832000, China"},{"name":"Heze Institute for Food and Drug Control, Heze 274000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingyuan","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resources and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832000, China"},{"name":"Department of Pharmacology, School of Pharmacy, Shihezi University, Shihezi 832000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziying","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resources and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832000, China"},{"name":"Department of Pharmacology, School of Pharmacy, Shihezi University, Shihezi 832000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Medical College, Shihezi University, Shihezi 832000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resources and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832000, China"},{"name":"Department of Pharmacology, School of Pharmacy, Shihezi University, Shihezi 832000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106780","DOI":"10.1016\/j.envint.2021.106780","article-title":"Release, transformation, and risk factors of polybrominated diphenyl ethers from landfills to the surrounding environments: A review","volume":"157","author":"Zhang","year":"2021","journal-title":"Environ. 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