Zinc Exposure Causes Disulfidptosis to Induce Miscarriage by Up-Regulating GATA1/METTL1/SLC7A11 Axis

  • Adv Sci (Weinh). 2026 May 7:e14513. doi: 10.1002/advs.202514513.
Wenxin Huang  1 ,  Yi Sun  1 ,  Yanxin Wang  1 ,  Haijun Yan  1 ,  Xiaoping Yue  2 ,  Weidong Wu  3 ,  Xueyu Chen  4 ,  Jinfang Zhang  5 ,  Yanbing Lin  1 ,  Qiong Lei  6 ,  Nan Ji  7 ,  Shuaishuai Xing  1 ,  Liqin Zeng  5 ,  Qingzheng Kang  1 ,  Depeng Zhao  4 ,  Geng Guo  8 ,  Huidong Zhang  1
Affiliations
  • 1. Research Center for Environment and Female Reproductive Health, Biological Laboratory of Hetao Cooperation Zone, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  • 2. Institute of Flow Chemistry and Engineering, College of Chemistry and Materials, Jiangxi Normal University, Nanchang, Jiangxi, P. R. China.
  • 3. School of Public Health, Henan Medical University, Xinxiang, Henan Province, China.
  • 4. Department of Reproductive Medicine, Women and Children's Medical Center, Shenzhen School of Clinical Medicine, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong Province, China.
  • 5. Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China.
  • 6. Department of Obstetrics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China.
  • 7. Faculty of Health Sciences Building, University of Macau, Taipa, Macau, China.
  • 8. Department of Emergency, Cerebrovascular Disease Center, First Hospital of Shanxi Medical University, Taiyuan, China.
PMID: 42095470 DOI: 10.1002/advs.202514513
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 ZnCl2-exposed mouse models, and a ZnCl2-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.

Keywords
SLC7A11; Zn exposure; disulfidptosis; m7G RNA modification; unexplained miscarriage.
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