Beyond silkworms: translating molecular mechanisms of pesticide toxicity from Bombyx mori to lepidopteran pest management.

The domesticated silkworm (Bombyx mori) is an established model for investigating pesticide ecotoxicology in Lepidoptera. However, a systems-level integration of its molecular response networks across diverse pesticide classes is still lacking. This review synthesizes multi-omics, physiological, and biochemical data to construct a comprehensive framework for the toxicity of B. mori. Our analysis revealed that pesticide exposure universally disrupts energy homeostasis by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and dysregulating trehalose metabolism, culminating in severe ATP depletion. The resulting overproduction of ROS sequentially triggers major defense pathways, such as the PI3K/Akt, MAPK/CREB, and CncC/Keap1 pathways. These pathways coordinate the transcriptional activation of antioxidant enzymes and detoxification proteins, including P450s, GSTs, and CarEs, via ARE- and XRE-dependent mechanisms. Concurrently, pesticides induce autophagy-apoptosis crosstalk via calcium dysregulation and caspase cascade activation. This molecular disruption is compounded by the reshaping of the gut microbiota, characterized by the enrichment of opportunistic pathogens, such as Enterobacter, and the depletion of beneficial symbionts, such as Bifidobacterium, alongside the suppression of Toll/IMD/JAK-STAT immune signaling. This dual assault on immunity and metabolism creates a synergistic 'multi-hit' effect that dramatically increases susceptibility to pathogens, such as BmNPV. This integrated framework identifies the CncC-ARE axis, mitochondrial energy sensors, and gut microbiota-host interactions as central regulatory hubs and promising targets for intervention. By translating these mechanistic insights from silkworms to broader lepidopteran pests, this study provides a theoretical foundation for ecological risk assessment and biomarker discovery. Furthermore, it establishes a roadmap for developing targeted green pest management strategies with direct implications for advancing sustainable sericulture and precision pest control. © 2026 Society of Chemical Industry.