Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans.

Vitamin B12 (B12) deficiency is a critical problem worldwide. Such deficiency in infants has long been known to increase the propensity to develop obesity and diabetes later in life through unclear mechanisms. Here, we establish a Caenorhabditis elegans model to study how early-life B12 impacts adult health. We find that early-life B12 deficiency causes increased lipogenesis and lipid peroxidation in adult worms, which in turn induces germline defects through ferroptosis. Mechanistically, we show the central role of the methionine cycle-SBP-1/SREBP1-lipogenesis axis in programming adult traits by early-life B12. Moreover, SBP-1/SREBP1 participates in a crucial feedback loop with NHR-114/HNF4 to maintain cellular B12 homeostasis. Inhibition of SBP-1/SREBP1-lipogenesis signaling and ferroptosis later in life can reverse disorders in adulthood when B12 cannot. Overall, this study provides mechanistic insights into the life-course effects of early-life B12 on the programming of adult health and identifies potential targets for future interventions for adiposity and infertility.