W Huang, Yi Sun, Yanxin Wang, Haijun Yan, Xiaoping Yue, Weidong Wu, X Y Chen, Jinfang Zhang, Yuxin Lin, Qiong Lei, Nan Ji, Shaojun Xing, Liqin Zeng, Qingzheng Kang, Depeng Zhao, Geng Guo, Haitao Zhang
ABSTRACT The pathogenesis of unexplained miscarriage (UM) is largely unclear. Environmental Zn pollution is widely present in various environments and inevitably ingested by pregnant women, which has shown reproductive toxicity. Disulfidptosis is a newly identified programmed cell death caused by excessive disulfide stress. Notably, the association, causation, and underlying mechanisms among Zn exposure, disulfidptosis, and unexplained miscarriage are completely unknown. In this study, based on two UM case‐control groups, four ZnCl 2 ‐exposed mouse models, and a ZnCl 2 ‐exposed trophoblast Swan 71 cell model, we obtain a consistent conclusion that excessive Zn exposure causes disulfidptosis and thus induces miscarriage by up‐regulating the GATA1/METTL1/SLC7A11 axis. In the mechanism, Zn exposure up‐regulates GATA1 expression levels, which promotes GATA1‐mediated METTL1 and SLC7A11 transcription. Meanwhile, Zn exposure also promotes METTL1‐mediated m7G modification on SLC7A11 mRNA and thus increases SLC7A11 mRNA stability. Ultimately, Zn exposure up‐regulates SLC7A11 expression levels at both transcription and post‐transcription levels and thus causes disulfidptosis. Knockdown of murine Slc7a11, Gata1, or Mettl1, or supplement with NADPH suppresses mouse placental disulfidptosis and alleviates mouse miscarriage. This study not only discovers pathogenesis and biological mechanisms of Zn exposure‐induced unexplained miscarriage but also provides potential targets, uncovering new health risk effects of Zn exposure in the environment‐health field.