Early-life redox perturbation programs intergenerational redox vulnerability through DAF-16/FOXO and SKN-1/Nrf2 signaling in Caenorhabditis elegans

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Early metabolic stress is a key factor influencing long term intergenerational adaptation in organisms. While excessive dietary methionine is known to disrupt one-carbon metabolism, it remains unclear whether early gestational methionine excess induces sustained epigenetic remodeling, thereby affecting redox stability in offspring. Using C. elegans as a model, we demonstrate that early gestational methionine excess in parental induces sustained metabolic stress in offspring, impairing their functional stability. This manifests as impaired motility, shortened lifespan, and elevated oxidative stress levels. Mechanistically, this intergenerational vulnerability is associated with metabolic reprogramming towards a serine-glycine-one-carbon axis. This leads to methyl donor imbalance and chromatin remodeling, characterized by SET-2/WDR-5.1 dependent H3K4 hypermethylation. Meanwhile, the stress response programs of DAF-16/FOXO and SKN-1/Nrf2 are restricted, thus affecting the redox adaptability of the offspring. Importantly, intervention with the dietary polyphenol epigallocatechin gallate (EGCG) can restore metabolic homeostasis and alleviate these chromatin and transcriptional restrictions. In summary, our findings reveal a metabolic and epigenetic framework by which early-life nutritional imbalances influence intergenerational redox resilience. We also emphasize that EGCG represents a potential nutritional strategy to alleviate metabolic stress caused by methionine excess. • Early gestational methionine overload acts as a metabolic stress that programs offspring redox vulnerability. • Metabolic-epigenetic coupling underlies intergenerational impairment of redox resilience and organismal fitness. • SET-2/WDR-5.1 mediated inhibition of H3K4me3 and DAF-16/SKN-1 is the cause of stress response. • EGCG reverses metabolic epigenetic coupling and restores redox adaptability

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