S-Adenosylmethionine Depletion as Potential Rate-Limiting Nexus of Redox–Epigenetic Crosstalk in Neural Tube Defects: A Mechanistic Theory and Experimental Hypothesis

S-adenosylmethionine (SAMe) depletion may represent a rate-limiting nexus linking oxidative/nitrosative stress to epigenetic failure during neurulation. In this review, we synthesize evidence that diverse teratogenic and metabolic insults, including valproic acid (VPA) exposure, maternal diabetes, and folate-dependent one-carbon imbalance, converge on a shared redox–metabolic–epigenetic axis that lowers SAMe availability, elevates S-adenosylhomocysteine, weakens glutathione buffering, and disrupts DNA and histone methylation/demethylation programs of genes required for neural tube closure. This framework explains how redox stress can impair key developmental pathways such as Wnt/β-catenin, sonic hedgehog, and Pax3 while promoting neuroepithelial apoptosis, abnormal proliferation, and failure of morphogenetic coordination. By integrating redox stress with chromatin regulation and one-carbon metabolism, the proposed model provides a unifying mechanism for neural tube defect pathogenesis and positions SAMe-centered metabolic control as a plausible therapeutic target. Definitive testing will require demonstrating that redox stress lowers embryonic SAMe before closure failure, that this precedes epigenetic dysregulation at neurulation genes, and that restoring SAMe rescues neural tube development in vivo. Indeed, our recent experiments showed that SAMe prevented brain oxidative/nitrosative stress and neural tube defects (NTDs) induced by VPA in ICR mouse embryos. Although most studies alongside our hypothesis are experimental and the entire causal pathway in humans remains to be established, increased oxidative stress, reduced SAMe, and reduced SAMe:SAH ratio were also described in human NTDs.