ATP-binding cassette B8 prevents endothelial dysfunction and atherosclerosis

ATP-binding cassette B8 (ABCB8) is a mitochondrial iron exporter known to prevent iron-dependent oxidative stress in cardiomyocytes and endothelial cells. However, the role of ABCB8 in endothelial and vascular function remains unclear. Here, we identified ABCB8 as a key regulator of vascular homeostasis. We found that loss of ABCB8 in endothelial cells triggers a pro-inflammatory transcriptional program, marked by upregulation of TGF-β isoforms and activation of TGF-β signalling. We show that TGF-β functions as an iron effector that drives mitochondrial reactive oxygen species (ROS) and mitochondrial damage, revealing a new ABCB8-iron-TGF-β axis in endothelial cells. In endothelial-specific inducible Abcb8 knockout mice (Abcb8^ECKO), ABCB8 deficiency leads to endothelial activation, pro-inflammatory transcriptional reprogramming of smooth muscle cells (SMCs), fibroblasts and immune cells. Combination of intravital imaging experiments with ex vivo treatment of aortae from Abcb8^ECKO with the iron chelator deferoxamine or TGF-β receptor I inhibitor SB431542 suggests that ABCB8 suppresses iron-dependent TGF-β-mediated vascular inflammation in the aorta. In agreement, endothelial ABCB8 deficiency exacerbates atherosclerosis and hypertension in Apoe^-/- knockout mice, uncovering a critical atheroprotective role for ABCB8 and supporting its therapeutic potential in vascular disease.