A multi-omics systems toxicology framework reveals amino acid–mediated stress adaptation to deltamethrin exposure in a yeast model

Abstract Deltamethrin (DLM) is a widely used synthetic pyrethroid insecticide known for its neurotoxic effects through interactions with voltage-gated sodium channels in insects. Despite its extensive application in agriculture, aquaculture, household settings, and animal husbandry, accumulating evidence indicates that DLM poses significant health risks to non-target organisms, including neurotoxicity, hepatotoxicity, nephrotoxicity, reproductive toxicity, metabolic disorders, and oxidative stress. Elucidating the cellular mode of action of DLM exposure is therefore critical. Previous studies have linked DLM exposure to endoplasmic reticulum (ER) stress and disrupted iron homeostasis; however, the metabolic adaptations underlying these responses remain poorly understood. In this study, we employed an integrated multi-omics approach to investigate the metabolic and transcriptomic responses of Saccharomyces cerevisiae exposed to non-lethal, chronic DLM doses over 30 days. Metabolomic profiling revealed significant alterations in amino acid metabolism, with notable accumulation of glycine and serine, amino acids known to mitigate ER stress. Transcriptomic analysis showed upregulation of iron deprivation response genes ( FRE3 , SIT1 ) and amino acid permease genes ( PUT4 , AGP1 ), indicating enhanced amino acid transport and iron uptake. Our findings demonstrate a coordinated adaptive response in which amino acid trafficking and iron homeostasis act in concert to alleviate DLM-induced ER stress, highlighting conserved stress adaptation mechanisms with potential relevance to human health.