Al Naggar_2025_Toxics_13_

The escalating challenge of resistance to insecticides among agricultural and public health pests poses a significant threat to global food security and vector-borne disease control. This review synthesizes current understanding of the molecular mechanisms underpinning resistance, including well-characterized pathways such as target-site mutations affecting nicotinic acetylcholine receptors (nAChRs), acetylcholinesterase (AChE), voltage-gated sodium channels (VGSCs), and gamma-aminobutyric acid (GABA) receptors, and metabolic detoxification mediated by cytochrome P450 monooxygenases (CYPs), esterases, and glutathione S-transferases (GSTs). Emerging resistance mechanisms are also explored, including protein sequestration by odorant-binding proteins and post-transcriptional regulation via non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Focused case studies on Aedes aegypti and Spodoptera frugiperda illustrate the complex interplay of genetic and biochemical adaptations driving resistance. In Ae. aegypti, voltage-gated sodium channel (VGSCs) mutations (V410L, V1016I, F1534C) combined with metabolic enzyme amplification confer resistance to pyrethroids, accompanied by notable fitness costs and ecological impacts on vector populations. In S. frugiperda, multiple resistance mechanisms, including overexpression of cytochrome P450 genes (e.g., CYP6AE43, CYP321A8), target-site mutations in ryanodine receptors (e.g., I4790K), and behavioral avoidance, have rapidly evolved across global populations, undermining the efficacy of diamide, organophosphate, and pyrethroid insecticides. The review further evaluates integrated pest management (IPM) strategies, emphasizing the role of biopesticides, biological control agents, including entomopathogenic fungi and parasitoids, and molecular diagnostics for resistance management. Taken together, this analysis underscores the urgent need for continuous molecular surveillance, the development of resistance-breaking technologies, and the implementation of sustainable, multifaceted interventions to safeguard the long-term efficacy of insecticides in both agricultural and public health contexts.