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Summary: Insects have an effective innate immune system to protect themselves against fungal invasion. Metarhizium employs a toxin-based strategy using a nonribosomal peptide called destruxin A (DA) to counteract the host immune response. However, the mechanism by which DA inhibits insect immunity is still unclear. Here, we identified 48 DA-binding proteins in silkworm hemolymph, with the binding affinity (KD) ranging from 2 to 420 μM. Among these proteins, hemocytin, an important immune factor, was determined to be the strongest DA-binding protein. DA binds to hemocytin and regulates its conformation in a multisite manner. Furthermore, DA exerts a significant inhibitory effect on hemocytin-mediated hemocyte aggregation. By disrupting the interaction between hemocytin, actin A3, and gelsolin, DA prevents the transformation of granules into vesicles in hemocytes. These vesicles are responsible for storing, maturing, and exocytosing hemocytin. Therefore, hemocytin secretion is reduced, and the formation of structures that promote aggregation in outer hemocytes is inhibited.