Akt-FoxO signaling drives co-adaptation to insecticide and host plant stresses in an herbivorous insect

• Eight P450 genes in N. lugens are regulated by Akt-FoxO signaling, activated by FoxO and recovered by Akt. • Recombinant CYP4CE1, CYP6ER1 and CYP439A2 metabolize different insecticides, indicating a role in insecticide resistance. • Recombinant CYP4C61 and CYP4C78 metabolize phytochemicals, indicating a role in host adaptation. • Akt-FoxO signaling guarantees the controllable expression of eight P450 genes. • The functional balance of P450s enabling herbivorous insects to adapt to insecticides and phytochemicals, respectively. Ongoing interactions between host and herbivorous insect trigger a co-evolutionary arms race. Genetic diversity within insects facilitates their adaptation to phytochemicals and their derivatives, including plant-derived insecticides. Cytochrome P450s play important roles in metabolizing phytochemicals and insecticides, due to their diversity and almost perfect evolution. This study aims to uncover a common molecular mechanism in herbivorous insects by investigating the role of kinase-transcription factor regulation of P450s in conferring tolerance to both insecticides and phytochemicals. RNA interference, transcriptome sequencing, insecticide, and phytochemical bioassays were conducted to validate the functions of Akt, FoxO, and candidate P450s. Dual-luciferase activity assays were employed to identify the regulation of P450s by the Akt-FoxO signaling pathway. Recombinant P450 enzymes were utilized to investigate the metabolism of insecticides and phytochemicals. We identified an Akt-FoxO signaling cascade, a representative of kinase-transcription factor pathways. This cascade mediates the expression of eight P450 enzymes involved in the metabolism of insecticides and phytochemicals in Nilaparvata lugens . These P450s are from different families and with different substrate selectivity, enabling them to respectively metabolize insecticides and phytochemicals with structure diversity. Nevertheless, the eight P450 genes were up-regulated by FoxO, which was inhibited in a higher cascade by Akt through phosphorylation. The discovery of the Akt-FoxO signaling pathway regulating a series of P450 genes elucidates the finely tuned regulatory mechanism in insects for adapting to phytochemicals and insecticides. These finding sheds light on the physiological balance maintained by these regulatory processes. The work provides the experimental evidence of co-adaptation to the stresses imposed by host plant and insecticide within the model of the kinase-TF involving various P450s. This model provides a comprehensive view of how pests adapt to multiple environmental stresses.