SAT1-Induced Spermidine Depletion Potentiates Food Allergy

Food allergies affect over 8% of children globally, with a 3.5-fold increase in incidence in the past two decades. However, disease-modifying therapies remain limited due to incomplete understanding of the underlying metabolic mechanisms. Thus, in this study, we aimed to demonstrate if spermidine/spermine N¹-acetyltransferase (SAT1)-mediated spermidine depletion drives food allergy pathogenesis through a previously unrecognized metabolic-immunological axis. Using a peanut allergy mouse model complemented by additional food allergen systems, we show that spermidine levels are significantly reduced during allergic responses, while exogenous supplementation attenuates disease severity. Moreover, SAT1 is markedly upregulated in allergic tissues, particularly in mast cells, where it promotes degranulation by suppressing autophagy. Mechanistically, SAT1 physically interacts with the long noncoding RNA Cdk19os to inhibit autophagy-related genes, including Atg5 and Atg7. Genetic or pharmacological targeting of the SAT1-Cdk19os-autophagy axis through SAT1/Cdk19os knockdown, spermidine supplementation, or autophagy induction effectively ameliorates allergic inflammation and reduces mast cell activation. These findings reveal that metabolic reprogramming actively drives food allergy development and identify tractable therapeutic targets and accessible dietary interventions in murine models. These results establish a conceptual framework for understanding the metabolic-immunological basis of food allergy and open new avenues for translational investigation into this increasingly prevalent condition.