Exposure to BDE-209 triggers necroptosis by activating the JAK2/STAT3 signaling pathway, thereby exacerbating neuroinflammation

Jing Yang; Liujiangshan Jiang; Haonan Ma; Yapei Zhu; Xuan Zhao; Tianyao Yang; Wei Liu

doi:10.1016/j.ecoenv.2025.118595

Exposure to BDE-209 triggers necroptosis by activating the JAK2/STAT3 signaling pathway, thereby exacerbating neuroinflammation

Ecotoxicol Environ Saf. 2025 Jun 27:302:118595. doi: 10.1016/j.ecoenv.2025.118595. Online ahead of print.

Authors

Jing Yang¹, Liujiangshan Jiang¹, Haonan Ma¹, Yapei Zhu¹, Xuan Zhao¹, Tianyao Yang¹, Wei Liu²

Affiliations

¹ Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China.
² Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China. Electronic address: liuw@cmu.edu.cn.

PMID: 40580630
DOI: 10.1016/j.ecoenv.2025.118595

Abstract

Polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, are extensively employed in industrial applications. Among these, decabromodiphenyl ether (BDE-209), the predominant congener, is widely incorporated into consumer materials owing to its exceptional flame-suppressive properties and thermal resistance. However, its environmental persistence and bioaccumulative potential classify BDE-209 as a prototypical persistent organic pollutant, with chronic exposure posing non-negligible risks to human health. Despite its prevalence, research addressing BDE-209-induced neurotoxicity remains limited, particularly regarding mechanistic pathways. This study explores BDE-209-triggered microglial necroptosis and its contribution to neuroinflammatory cascades, with a focus on the regulatory role of the JAK2/STAT3 signaling axis. Experimental analyses across cellular and animal models demonstrated that BDE-209 exposure provoked pronounced microglial activation and subsequent neuroinflammatory markers. Concurrently, necroptotic events were identified through hallmark molecular signatures: phosphorylation cascades involving RIPK1, RIPK3, and MLKL, coupled with cytolytic outcomes. Administration of the necroptosis inhibitor NEC-1 markedly attenuated BDE-209-associated neuroinflammation and cellular demise, underscoring the centrality of microglial necroptosis in this pathological process. Mechanistically, BDE-209 potentiates necrosome assembly by activating the JAK2/STAT3 pathway, as evidenced by reduced necroptotic activity upon AG490-mediated JAK2 inhibition. These findings collectively delineate a novel pathway wherein BDE-209 exacerbates neurotoxicity via JAK2/STAT3-driven microglial necroptosis, providing novel mechanistic insights for developing neuroprotective interventions.

Keywords: BDE-209; JAK2/STAT3; Necroptosis; Neuroinflammation; Neurotoxicity.