Mapping the Ferroptosis Signaling Network in Lung-Heart Axis Relevant to the Exacerbation of Atherosclerosis

Lung injury is a risk factor for atherosclerotic cardiovascular diseases, and both conditions share a common pathogenesis that encompasses ferroptosis. These cell death events occur consecutively throughout the tissue over considerable distances, raising the question of how ferroptosis is synchronized spatially and temporally. Herein, we developed near-infrared fluorescent probes, Cy-F-1 and Cy-F-2, to map the ferroptosis signaling network between lung injury and atherosclerosis by tracing ferrous ions. Upon exposure to cigarette smoke (CS), in situ imaging revealed that ferroptosis was initiated and propagated across the lung to aortic plaque regions in rats on a high-fat diet. These molecules were capable of traversing vast distances to trigger a potent ferroptosis response in macrophage foam cells residing within AS plaques. The contiguous exacerbation of ferroptosis events modulated lipid metabolism pathways through alterations in the expression of intracellular ATP-binding cassette transporters, impeding lipid efflux and intensifying the progression of atherosclerosis.