m6A‐Driven Pexophagy Triggers Placental Ferroptosis to Impair Fetal Growth Upon Environmental Stress
4 affiliations
- 1Department of Toxicology School of Public Health Anhui Medical University Hefei China
- 2Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes Hefei China
- 3The Fourth Affiliated Hospital of Anhui Medical University Anhui Medical University Hefei China
- 4Department of Rehabilitation Medicine, and the Second Affiliated Hospital of Anhui Medical University Hefei China
Abstract
The role and underlying mechanisms of placental ferroptosis in fetal growth restriction (FGR) induced by environmental stress remain poorly understood. Our population‐based study showed elevated ferroptosis levels in all‐cause FGR placentae. Environmental stressor cadmium (Cd) was used to generate an FGR mouse model, which exhibited elevated placental ferroptosis. Ferroptosis inhibitor ferrostatin‐1 reversed environmental Cd‐induced FGR. Targeted oxidized lipidomics identified the peroxisome as a target organelle for prenatal Cd‐induced placental ferroptosis. Furthermore, Cd induced excessive activation of PEX5‐dependent pexophagy in placentae. By establishing a placental Pex5‐knockdown mouse, pexophagy was confirmed to drive environmental Cd‐induced placental ferroptosis. Mechanistically, pexophagy drives the degradation of the H2O2‐scavenging enzyme and the fatty‐acid β‐oxidation enzymes, thereby causing lipid peroxidation and placental ferroptosis. Notably, environmental Cd upregulated PEX2, an E3 ligase mediating PEX5 monoubiquitination, thereby driving pexophagy and placental ferroptosis. Furthermore, METTL14‐mediated m6A modification enhanced the stability of placental PEX2 mRNA in an ELAVL1‐dependent manner under environmental Cd. SAH, a METTL14 inhibitor, alleviated Cd‐induced placental pexophagy, ferroptosis, and FGR. High‐temperature also decreased GPX4 and increased PEX2, PEX5, and METTL14 in placentae. Overall, our findings uncover a novel m6A‐PEX2‐PEX5 axis driving pexophagy‐dependent placental ferroptosis, offering placental pexophagy as a therapeutic target for FGR and fetal‐origin adult diseases.
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BibTeX
@article{zhang2026m6adriven,
title = {{m6A‐Driven Pexophagy Triggers Placental Ferroptosis to Impair Fetal Growth Upon Environmental Stress}},
author = {Xin‐Xin Zhang and Ye‐Xin Luo and Cheng‐Fang Sun and Rui Pan and Yu‐Xi Wu and Zhi Yuan and Xin‐Run Wang and Xu‐Dong Zhang and Lan‐Lan Wu and Xiang‐Yu Yao and Zhan‐Dong Song and Wei Chang and Tian Wei and Pan‐Yuan Cai and Tian‐Ci Zhang and Yong‐Wei Xiong and De‐Xiang Xu and Hua Wang and Hua‐Long Zhu},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77068},
url = {https://doi.org/10.1002/advs.77068},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - m6A‐Driven Pexophagy Triggers Placental Ferroptosis to Impair Fetal Growth Upon Environmental Stress
AU - Xin‐Xin Zhang
AU - Ye‐Xin Luo
AU - Cheng‐Fang Sun
AU - Rui Pan
AU - Yu‐Xi Wu
AU - Zhi Yuan
AU - Xin‐Run Wang
AU - Xu‐Dong Zhang
AU - Lan‐Lan Wu
AU - Xiang‐Yu Yao
AU - Zhan‐Dong Song
AU - Wei Chang
AU - Tian Wei
AU - Pan‐Yuan Cai
AU - Tian‐Ci Zhang
AU - Yong‐Wei Xiong
AU - De‐Xiang Xu
AU - Hua Wang
AU - Hua‐Long Zhu
PY - 2026
DA - 2026/08/12
JO - Advanced Science
DO - 10.1002/advs.77068
UR - https://doi.org/10.1002/advs.77068
AB - The role and underlying mechanisms of placental ferroptosis in fetal growth restriction (FGR) induced by environmental stress remain poorly understood. Our population‐based study showed elevated ferroptosis levels in all‐cause FGR placentae. Environmental stressor cadmium (Cd) was used to generate an FGR mouse model, which exhibited elevated placental ferroptosis. Ferroptosis inhibitor ferrostatin‐1 reversed environmental Cd‐induced FGR. Targeted oxidized lipidomics identified the peroxisome as a target organelle for prenatal Cd‐induced placental ferroptosis. Furthermore, Cd induced excessive activation of PEX5‐dependent pexophagy in placentae. By establishing a placental Pex5‐knockdown mouse, pexophagy was confirmed to drive environmental Cd‐induced placental ferroptosis. Mechanistically, pexophagy drives the degradation of the H2O2‐scavenging enzyme and the fatty‐acid β‐oxidation enzymes, thereby causing lipid peroxidation and placental ferroptosis. Notably, environmental Cd upregulated PEX2, an E3 ligase mediating PEX5 monoubiquitination, thereby driving pexophagy and placental ferroptosis. Furthermore, METTL14‐mediated m6A modification enhanced the stability of placental PEX2 mRNA in an ELAVL1‐dependent manner under environmental Cd. SAH, a METTL14 inhibitor, alleviated Cd‐induced placental pexophagy, ferroptosis, and FGR. High‐temperature also decreased GPX4 and increased PEX2, PEX5, and METTL14 in placentae. Overall, our findings uncover a novel m6A‐PEX2‐PEX5 axis driving pexophagy‐dependent placental ferroptosis, offering placental pexophagy as a therapeutic target for FGR and fetal‐origin adult diseases.
SN - 2198-3844
ER -