Stage-resolved Metabolomics Reveals the Methionine Cycle As a Key Regulator of Aedes Aegypti Development and Dengue Virus Susceptibility

Developmental transitions in the mosquito Aedes aegypti are central to vector competence and disease transmission, yet the underlying metabolic programs remain poorly defined. Here, we use untargeted metabolomics, gene expression analysis, and functional assays to delineate stage-specific metabolic fingerprints across the mosquito life cycle, from egg and larva to pupa and adult. Our profiling of the larval diet reveals comprehensive provisioning of essential nutrients, including B vitamins critical for development. Metabolomic analyses uncover distinct, stage-specific signatures, with the larval stage exhibiting a pronounced enrichment of methionine cycle metabolites and maximal methylation capacity. Notably, while S-adenosylmethionine (SAM) and related metabolites peak in larvae, the transcription of the methionine cycle and histone methyltransferase genes is highest in adults. Functional disruption of the methionine cycle in mosquito cells reveals network-level robustness and regulatory crosstalk within the pathway. However, we also identify a specific vulnerability: silencing the gene adenosylhomocysteinase (ahcy) enhances dengue virus 1 replication and infectious particle production. Collectively, our findings identify the methionine cycle as a metabolic epigenetic hub that integrates nutrition, development, and viral susceptibility, and highlight the larval stage as a strategic target for novel mosquito-control strategies. ### Competing Interest Statement The authors have declared no competing interest.