2,2’,4,4’-Tetrabromodiphenyl ether (BDE−47)–HSD17B10 interaction drives atherosclerotic plaque instability by inducing mitochondrial dysfunction

The formation and death of foam cells are pivotal contributors to atherosclerotic plaque expansion and instability, leading to acute cardiovascular events. In addition to genetic influence, environmental pollution plays a crucial role in driving macrophage-to-foam cell differentiation. To examine the role and mechanism of 2,2’,4,4’-tetrabromodiphenyl ether (BDE−47), a widely existing organic pollutant, in atherosclerosis pathology. Apolipoprotein E-deficient ( Apoe –/– ) mice were fed on a 1.25% high-cholesterol diet for 12 weeks to induce atherosclerosis with or without BDE−47 exposure. Bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages (hTDMs) were used to explore the underlying mechanism affected by BDE−47 exposure during foam cell formation. BDE−47 exposure specifically upregulates CD36 expression to accelerate foam cell formation and death, leading to plaque destabilization. Mechanically, BDE−47 interacts with type 10 17β-hydroxysteroid dehydrogenase (HSD17B10) to disrupt its binding affinity to cyclophilin D (CypD), leading to mitochondrial dysfunction and subsequent nuclear factor κB (NF-κB) signaling activation, which ultimately forces CD36 expression. Administration of the CypD inhibitor C105SR alleviated BDE−47 exposure-induced mitochondrial dysfunction within foam cells and limited the progression of atherosclerosis. Our data elucidate the critical role of BDE−47 exposure in accelerating atherosclerosis progression and the underlying molecular mechanisms, providing novel insights for therapeutic strategies that target environmental cues of BDE−47.