m6A-Driven Pexophagy Triggers Placental Ferroptosis to Impair Fetal Growth Upon Environmental Stress

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.