CYP4G paralog divergence underlies pest resilience to insecticides and warming climate

Understanding the synergistic adaptation of insect pests to climate warming and insecticide exposure is critical for sustainable pest management. This study elucidates the molecular basis of this resilience in the cosmopolitan pest Tribolium castaneum, revealing that functional divergence of CYP4G paralogs is a central mechanism. Through integrated functional genomics, metabolomics, and phenotypic analyses, we demonstrate that two paralogs, TcCYP4G7 and TcCYP4G15, have evolved distinct specializations to orchestrate cross-tolerance. TcCYP4G7 enhances resilience to pyrethroid insecticides by upregulating detoxification enzymes and concurrently modulating amino acid metabolism to increase cuticular thickness. This dual action reduces insecticide penetration while improving heat tolerance. In contrast, TcCYP4G15 confers protection against organophosphate insecticides by reinforcing the neurological barrier through enhanced acetylcholinesterase activity and modifying cuticular lipid composition. Crucially, both pathways are enhanced under heat stress. RNAi-mediated knockdown of either gene disrupted this synergistic adaptation, compromising cuticular integrity and reprogramming downstream gene networks. Our findings establish that CYP4G paralog divergence underpins a multifaceted adaptation strategy, providing a molecular framework for predicting and countering pest resilience under combined environmental stresses.