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

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.