Xanthotoxin‐triggered HR51 suppression derepresses detoxification genes to drive metabolic adaptation in Spodoptera litura

BACKGROUND: The enhanced capacity for metabolic detoxification is a key adaptive strategy enabling insects to tolerate plant secondary metabolites (PSMs). This adaptation is largely driven by the transcriptional regulation of detoxification genes. Our previous work established the critical involvement of specific detoxification enzymes in xanthotoxin metabolism in Spodoptera litura. In the present study, we aimed to identify and characterize the transcription factors responsible for orchestrating detoxification gene expression. RESULTS: RNA-sequencing analysis revealed that, alongside transcription factors induced by xanthotoxin, the nuclear receptor hormone receptor-like 51 (HR51) was uniquely and consistently down-regulated in both the midgut and fat body of S. litura. To elucidate the role of HR51 in xanthotoxin detoxification, we generated HR51-knockout mutants using CRISPR/Cas9-mediated gene editing. These mutants displayed markedly enhanced tolerance to xanthotoxin, accompanied by the up-regulation of detoxification genes responsible for its metabolism. Mechanistic studies through dual-luciferase reporter assays coupled with site-directed mutagenesis demonstrated that HR51 suppressed the expression of detoxification genes through binding to the specific cis-acting element within their promoter. CONCLUSION: This study uncovers a novel derepression mechanism in which suppression of the transcriptional repressor HR51 alleviates its inhibition on detoxification genes, thereby facilitating S. litura adaptation to xanthotoxin. These findings advance our understanding of insect counter-defense against PSMs and highlight HR51 as a promising molecular target for the development of innovative pest management strategies. © 2026 Society of Chemical Industry.