Daidzein Mitigates Nicotine‐Induced Atherogenesis via Nrf2/ROS/TXNIP‐Dependent Inhibition of Macrophage Pyroptosis and Lipid Accumulation

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ABSTRACT Food‐derived bioactive components play a crucial role in the prevention of cardiovascular diseases. Daidzein (DAI), a soy isoflavone, possesses notable cardioprotective potential; however, its precise role in nicotine‐induced atherosclerosis (AS) and its underlying mechanisms remain unclear. This study explored whether DAI protects against AS by modulating macrophage pyroptosis and lipid metabolism via redox‐sensitive signaling pathways. In human acute monocytic leukemia cell line (THP‐1)‐derived macrophages, DAI alleviated nicotine‐induced pyroptosis, as evidenced by the downregulation of NOD‐like receptor family pyrin domain‐containing 3 (NLRP3), ASC, cleaved caspase‐1, and gasdermin D (GSDMD)‐N, accompanied by reduced secretion of interleukin (IL)‐1β, IL‐6, and IL‐18, and decreased lactate dehydrogenase (LDH) release and caspase‐1 activity. DAI also enhanced (7‐nitrobenz‐2‐oxa‐1,3‐diazole)‐cholesterol (NBD)‐cholesterol efflux, suppressed DiI‐labeled oxidized low‐density lipoprotein (DiI‐ox‐LDL) uptake, and mitigated intracellular lipid droplet accumulation. Mechanistically, silencing nuclear factor erythroid 2–related factor 2 (Nrf2), inducing reactive oxygen species (ROS), or overexpressing thioredoxin‐interacting protein (TXNIP) abolished the protective effects of DAI, confirming the involvement of the Nrf2/ROS/TXNIP pathway. In nicotine‐exposed apolipoprotein E‐deficient (apoE −/− ) mice, DAI upregulated vascular Nrf2, downregulated TXNIP and pyroptosis‐related proteins, improved plasma lipid profiles, alleviated systemic inflammation, and reduced aortic plaque formation, with no obvious adverse effects observed under the experimental conditions used. Collectively, DAI attenuated macrophage pyroptosis and lipid accumulation via the Nrf2/ROS/TXNIP pathway, thereby mitigating nicotine‐induced atherogenesis. These findings provide preclinical evidence for the potential of DAI as a food‐derived bioactive compound for smoking‐related AS.

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