The diversity of host plants is an important reason for the global spread of Hyphantria cunea. However, no studies have explored the role of the antioxidant defense system with catalase (CAT) as the core at the molecular level in the adaptation of the H. cunea to host plant secondary metabolites. Herein, the purpose is to explore how HcCAT2, highly expressed in cytisine- or coumarin-treated H. cunea larvae, mediates the adaptation of H. cunea to cytisine and coumarin, and to develop nucleic acid pesticides targeting HcCAT2. Findings revealed that H. cunea larvae treated with dsHcCAT2 alongside cytisine or coumarin exhibited significantly reduced body weight, survival rate, and expression levels of growth-related genes, energy metabolism genes, and oxidative damage regulatory genes compared to treated with cytisine or coumarin alone. HcCAT2 overexpression enhanced cell viability, lowered apoptosis rates, Ca