Multiomics Approaches to Study the Contact Toxicity and Mechanisms of Aliphatic Ketones and Aldehydes against <i>Tribolium castaneum</i>

<i>Tribolium castaneum</i> is a major pest of stored grain products. This research aimed to investigate how structural variation in plant-derived aliphatic ketones and aldehydes influenced contact toxicity against <i>T. castaneum</i>. 2-Dodecanone (Do, C₁₂) demonstrated the greatest contact toxicity (LD₅₀ = 14.9 μg/larva), substantially exceeding its isomer dodecanal (Da, LD₅₀ = 30.0 μg/larva). Toxicity peaked at 12 carbons and declined as chain length increased or decreased, with 2-heptanone (Ho, C₇) being the least active (LD₅₀ = 43.5 μg/larva). Integrated transcriptomic, proteomic, metabolomic, and RNA-interference analyses revealed compound-specific mechanisms. Do penetrated the cuticle efficiently owing to its higher lipophilicity, activating phase I detoxification (CYP6BQ7, CYP345A1, CYP345D2) and hormone biosynthesis (FDa). Da induced phase 0 handling through OBP-C11 and downregulated cuticle protein via LCPF-like. Ho triggered structural defenses, with SSP2-like upregulation and CSP10 downregulation. Metabolomics showed Da predominantly produced organic acids and derivatives, while Do and Ho yielded lipids and lipid-like metabolites, reflecting divergent biotransformation routes. These findings clarify structure-activity relationships and identify molecular targets for designing safe, effective grain protectants.