Polystyrene nanoplastics induce fetal growth restriction via a novel NMNAT3 depletion cascade disrupting placental mitochondrial energetics and activating ferritinophagic ferroptosis

The escalating environmental prevalence of micro- and nanoplastics (NPs) poses a growing threat to maternal-fetal health, with the placenta being a particularly vulnerable interface. However, the precise metabolic mechanisms by which NPs compromise placental function and contribute to adverse pregnancy outcomes remain poorly understood. This study, employing untargeted metabolomics, reveals that gestational exposure to polystyrene nanoplastics (PS-NPs) severely disrupts placental nicotinamide (NAM) metabolism and impairs mitochondrial energetics. A key mechanistic discovery is the central role of NMNAT3, a mitochondrial NAD synthase. PS-NPs exposure downregulated NMNAT3, leading to NAD depletion, mitochondrial dysfunction, oxidative stress, and lipid peroxidation in trophoblasts, which collectively triggered ferritinophagy-mediated ferroptosis. Notably, NMNAT3 overexpression rescued these defects by suppressing ferritinophagy, limiting cytotoxic iron release, and inhibiting ferroptosis. Importantly, NAM, as a metabolic modulator, can inhibit ferroptosis and improve pregnancy outcomes by restoring NAD homeostasis. Collectively, our findings delineate a novel pathogenic axis wherein PS-NPs impair placental health via NMNAT3-dependent disruption of NAM metabolism and iron homeostasis, highlighting NAM supplementation as potential strategies to counteract nanoplastic-induced reproductive toxicity.