Beyond gut and neural mechanisms: A multi-organ system perspective on insecticide resistance

Insecticide resistance has usually been studied through isolated mechanisms, primarily focusing on target-site insensitivity, metabolism and cuticular modifications. However, substantial gaps remain in understanding how various organs and systems interact and work together to contribute to resistance. Emerging research, highlights resistance as a multi-organ phenomenon, where multiple physiological systems contribute to detoxification, toxin transport, immune modulation, trade-offs, stress adaptation and survival under insecticidal pressure. This review explores the role of fat body metabolism, circulatory transport, transgenerational effects, respiratory adjustments, Malpighian tubule excretion and endocrine regulation in shaping insecticide resistance. These organ systems engage in complex inter-organ signaling and compensatory mechanisms, allowing resistant insects to mitigate the toxic effects of insecticides while maintaining fitness. Advancements in research such as multi-omics technologies, single-cell RNA sequencing and advanced imaging techniques can provide deeper insights into these systemic adaptations and help develop more precise and targeted management strategies. However, challenges remain in deciphering inter-organ communication, identifying tissue-specific resistance markers, and developing field-ready diagnostic methods. Addressing these gaps through functional genomics, systems biology, and microbiome-targeted strategies will be crucial for sustainable pest control. By integrating multi-organ system perspectives, future research can develop more effective and targeted resistance management approaches, ensuring the long-term efficacy of insecticides used.