Insecticides are widely used in pest control; however, the increasing development of resistance in pests poses a significant global challenge. Nuclear receptors (NRs), ligand-dependent transcription factors, regulate the expression of genes involved in diverse metabolic processes, including development, detoxification, and innate immunity. However, the role of NRs in the detoxification processes of the brown planthopper, Nilaparvata lugens (N. lugens), remains poorly understood. Here, we show that estrogen-related receptor (NlERR) is a novel regulator of cytochrome P450 (CYP) genes for imidacloprid (IMD) resistance in N. lugens. Interestingly, the NlERR was significantly overexpressed in IMD-resistant strains. Genome-wide transcriptome analysis of NlERR-deficient N. lugens showed a positive correlation between the NlERR and the transcription of genes associated with detoxification metabolism. In addition, IMD treatment significantly increased the gene expression of phase I P450 enzymes in suspectable N. lugens, which was reversed by NlERR knockdown. Moreover, chromatin immunoprecipitation analysis confirmed that the NlERR directly binds to the ERR-response elements on the promoter of the CYP4CE1 gene. Consequently, NlERR knockdown in IMD-resistant strains significantly reduced the survival rate following IMD treatment and decreased expression of its target genes, CYP4CE1 and CYP6CW1. Finally, silencing either CYP4CE1 or CYP6CW1 in IMD-resistant strains significantly decreased the survival rate of the strains treated with IMD treatment. These findings establish NlERR as a key genetic factor for conferring IMD resistance in the N. lugens. Selectively controlling NlERR activity with a specific modulator will provide critical insights for developing new strategies to combat insecticide resistance in the N. lugens.
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