Bt Research 2025, Vol.16, No.6, 234-241 http://microbescipublisher.com/index.php/bt 235 The objective of this study is to sort out the molecular mechanisms, coping strategies and the latest technological advancements of Bt toxin resistance. We will focus on introducing how to enhance the binding force between toxins and receptors by modifying their structures, how to optimize the design of multi-toxin crops, and how to promote a more adaptive integrated management system in the context of the continuous evolution of resistance. It is hoped that these contents can provide a theoretical basis for the continuous and safe application of Bt crops and biopesticides, and also offer technical reserves for the stable development of future agriculture and global food security. 2 Mechanisms of Insect Resistance to Bt Toxins 2.1 Mutations in toxin receptors and reduced binding affinity (e.g., CAD, APN, ALP) Not all insects are naturally resistant to Bt toxins, but in some populations, when some key protein structures change, trouble follows. Midgut receptors such as cadmucin (CAD), aminopeptidase N (APN), and alkaline phosphatase (ALP) are originally the "targets" of toxins. Once these proteins mutate or their expression levels decline, Bt toxins are difficult to accurately "hit", and the effect is reduced (Jurat-Fuentes et al., 2021; Liu et al., 2022; Hu et al., 2025). For instance, some studies have found that Cry2Ab toxin is significantly less effective against cotton bollworms with ABCA2 mutations, indicating that receptor proteins play a crucial role in resistance formation (Tay et al., 2015). Of course, this does not mean that every resistance is related to receptor mutations, but this mechanism of "toxins not hitting the target" has indeed been widely observed, and the inhibition of Bt toxins is also very obvious. 2.2 Activation of detoxification and efflux mechanisms Even if the toxin can successfully enter the insect's body at the beginning, it doesn't mean that it can successfully complete the "task". Some insects activate another set of defense mechanisms - allowing toxins to be dismantled or expelled before they even take effect. For instance, in some insects, the activity of intestinal protease has increased, and the Bt pretoxin has been decomposed before it is activated. In addition, the levels of detoxifying enzymes or excretion transport proteins will also rise, making it difficult for toxins to accumulate to lethal concentrations. The small cabbage moth is a typical example. They can regulate the expression of these "detoxification factors" in the midgut through the MAPK signaling pathway (Guo et al., 2020). Moreover, this regulation has little impact on the survival of insects themselves. That is to say, they "make very little effort but have strong resistance". Therefore, such biochemical countermeasures not only increase the complexity of the resistance mechanism but also make the prevention and control of Bt resistance more challenging (Wang et al., 2025). 2.3 Behavioral adaptations and physiological barriers Sometimes, insects do not rely on complex molecular regulation; they simply "bypass the problem". For instance, some insects will change their feeding patterns. They no longer eat plants containing Bt toxins in large quantities but instead consume them in small amounts, at different times, and try to minimize their intake. Moreover, when the pH value of the midgut or the composition of the peristaltic membrane changes, the solubility and penetration ability of toxins will also be affected, directly reducing the effect of toxins. Furthermore, some insects can enhance their own immune levels, such as secreting more antimicrobial peptides and releasing reactive oxygen species, to counter the attack of Bt toxins (Xiao et al., 2023). Although these behavioral and physiological changes may not seem so "high-end", when combined with molecular mechanisms, they often cause considerable interference to the control effect of Bt, making continuous pest management more challenging. 3 Resistance Monitoring and Evolutionary Trends 3.1 Laboratory and field-based resistance assessment methods Whether insects develop resistance to Bt toxins cannot be determined solely by the naked eye in the field. Laboratory tests often detect early signs earlier. For instance, in a controlled environment, expose pests to a standard concentration of Bt toxin to see what the mortality rate is, or test the allele frequencies that may cause resistance. Field investigations are of course indispensable, such as whether the pest density in the area where Bt
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