Multi-omics analysis reveals AaaaNAT1 as a critical regulator of physiological homeostasis in Aedes aegypti

Physiological homeostasis is fundamental to vector competence in Aedes aegypti . Using RNA interference coupled with integrated multi-omics analysis (transcriptome, proteome, and metabolome), we elucidated the critical role of Arylalkylamine N-acetyltransferase-1 of Aedes aegypti (AaaaNAT) in maintaining salivary gland homeostasis and systemic physiological integrity. AaaaNAT1 knockdown precipitated genome-wide transcriptomic repression in salivary glands, concurrent suppression of energy metabolism, activation of compensatory protein synthesis, and extensive metabolic reprogramming. These molecular perturbations manifested as severely compromised immune defense, evidenced by rapid mortality upon bacterial challenge, and dramatically enhanced insecticide susceptibility. Notably, the LC50 of chlorpyrifos decreased from 7.90 μg/mL to 0.93 μg/mL, representing an ∼8-fold sensitivity increase. Multi-omics integration further revealed that AaaaNAT1 dysfunction disrupts sphingolipid signaling and impairs detoxification pathways, ultimately driving physiological collapse. Our findings establish AaaaNAT1 as a pivotal orchestrator of physiological homeostasis and stress adaptation, positioning it as a high-value molecular target for innovative vector control strategies. This work provides a robust framework for identifying critical gene targets and lays a solid foundation for translational applications in mosquito-borne disease prevention. © 2026 Elsevier Ltd.