Novel function of arylalkalamine <i>N‐</i> acetyltransferase‐1 in modulating host coagulation and blood feeding in <i>Aedes aegypti</i>

Abstract During blood feeding, mosquitoes modulate the host's coagulation response via salivary proteins to facilitate their blood intake. Arylalkylamine N‐ acetyltransferase‐1 (aaNAT1) exhibits significant expression levels in the salivary glands of Aedes aegypti . While AaaaNAT1 deletion impairs anticoagulant function, the underlying mechanism has remained elusive. Here we combined in vitro and in vivo experiments to elucidate this mechanism. Recombinant AaaaNAT1, expressed in an E. coli ‐based prokaryotic system, dose‐dependently suppressed human platelet aggregation and prolonged both clot‐time and fibrinolysis in calibrated thromboelastography assays. When the AaaaNAT1 protein is injected into mice via intramuscular injection, it will rapidly acetylate the norepinephrine in the surrounding tissue microenvironment, thereby inhibiting platelet aggregation. Meanwhile, RNAi‐mediated silencing of AaaaNAT1 in female mosquitoes reduced endogenous octopamine levels, downregulated the octopamine receptor, and more than doubled the time required to locate a host and complete feeding. We have uncovered a dual‐function strategy that inhibits mosquito blood‐sucking: dual modulation of host hemostasis and vector behavior by a single enzyme. Our findings demonstrate that AaaaNAT1 functions as a salivary anticoagulant by acetylating norepinephrine while simultaneously governing host‐seeking via octopamine signaling. This establishes AaaaNAT1 as a unique target that can be exploited for next‐generation vector control, extending its canonical roles beyond pigment synthesis and immunity to a novel, druggable node for vector control.