Integrative epidemiology and multi-omics reveal a frailty-associated ACKR1 redox axis linking cadmium exposure to...

Chronic cadmium (Cd) exposure is increasingly associated with elevated cardiovascular disease (CVD) risk; however, the redox-dependent mechanisms underlying this association remain poorly defined. Epidemiological evidence indicates that frailty acts as a biological amplifier of Cd-related cardiovascular vulnerability, characterized by heightened oxidative stress, inflammation, and endothelial dysfunction. To elucidate these mechanisms, we focused on atherosclerosis-the pathological hallmark of CVD-and integrated population-based analyses with multi-omics approaches. Mendelian randomization confirmed a potential causal relationship between Cd exposure and CVD risk. Spatial and single-cell transcriptomic profiling of atherosclerotic tissues revealed that Cd exposure and frailty signatures were preferentially enriched within macrophage-dense regions exhibiting pronounced oxidative stress. Among macrophage subsets, the MP1 meta-program displayed the highest Cd- and frailty-associated gene scores and engaged in intense crosstalk with endothelial cells via the CXCL2/3/8-ACKR1 ligand-receptor axis (C-X-C motif chemokine ligand 2/3/8-atypical chemokine receptor 1). Mechanistically, Cd exposure reprogrammed macrophage metabolic and inflammatory states, driving excessive chemokine release and sustained ACKR1-dependent macrophage-endothelial interactions, which in turn promoted pathological accumulation of reactive oxygen species (ROS) and redox imbalance within atherosclerotic lesions. Importantly, blockade of ACKR1 markedly attenuated inflammatory signaling, reduced ROS accumulation, and alleviated vascular tissue injury. Collectively, these findings define a previously unrecognized Cd-frailty-ACKR1 redox-inflammatory axis that mechanistically links environmental metal exposure to oxidative vascular injury and highlights ACKR1 as a potential therapeutic target for mitigating pollution-associated cardiovascular disease.