As a major bioactive compound from grapes, piceatannol has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In this study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared to control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, GSDMD, IL-18, IL-1b and NLRP3. Moreover, we investigated the role of miR-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of Nrf2, indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. This study is the first time to identify miR-200a as a candidate target in atherosclerosis and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of atherosclerosis.

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