Lighting up Ferroptosis Propagating via the Lung‐Heart Axis Exacerbates Cardiovascular Disease Through in Situ Imaging

ABSTRACT Cigarette smoke (CS)‐induced lung injury is a risk factor for atherosclerotic cardiovascular diseases (ASCVDs), with both diseases sharing a common pathogenesis that encompasses ferroptosis. Studies have shown that ferroptosis can propagate in a wave‐like manner across cell populations; however, whether and how this propagation participates in the cross‐organ communication between lung injury and ASCVDs remains unknown. Here we developed two near‐infrared fluorescent probes, Cy‐F‐1 and Cy‐F‐2, with lung‐targeting and plaque‐targeting properties, respectively. Utilizing in vivo molecular fluorescence imaging, we explored the ferroptosis communication between lung injury and atherosclerosis (AS) by directly observing the dynamics of the ferroptosis marker, Fe 2+ . Imaging results found that upon exposure to CS, ferroptosis was initiated and propagated across the lung to aortic plaque regions in AS rats. In combination with biochemical and transcriptomic analyses, we have for the first time mapped a ferroptosis‐mediated signaling network linking both diseases: CS‐induced ROS accumulation → Nrf2‐GPX4 axis destruction → labile iron pool expansion → lung epithelial cells ferroptosis → lung inflammation injury → TNF‐α/IL‐1β/IL‐6 release → foam cell ferroptosis → ABCA1/ABCG1 downregulation → exacerbated AS. This study discovers the wave‐guided role of ferroptosis in the crosstalk between lung injury and AS, revealing the molecular mechanism of smoking‐aggravated ASCVDs.