| Summary: | The American cockroach, <i>Periplaneta americana</i> (L.), is a notorious urban pest. It has developed insecticidal resistance to commonly used insecticides. Cantharidin (CTD) is a defensive toxin derived from blister beetles. It has been verified to have insecticidal toxicity in a range of pests. In this study, we determined the ingestion toxicity of CTD and norcantharidin (NCTD) to <i>P. americana</i> to test whether they had the potential to be effective against <i>P. americana</i>. Bioassays revealed that CTD produces toxicity against <i>P. americana</i>. The median lethal concentration (LC<sub>50</sub>) value of CTD was 50.92 μg/mL, while NCTD displayed nearly no toxicity against <i>P. americana</i>. The inhibition assays of serine/threonine protein phosphatases (PSPs) in <i>P. americana</i> indicated that CTD and NCTD could inhibit PSPs. The value of the half maximal inhibitory concentration (IC<sub>50</sub>) of CTD was 7.21 ± 0.94 μM, whereas that of NCTD was higher, at 31.65 ± 3.87 μM. Furthermore, the inhibition effect of CTD on the serine/threonine protein phosphatase type 5 of <i>P. americana</i> (PaPP5) was superior to that of NCTD. Specifically, the IC<sub>50</sub> of CTD reached 0.39 ± 0.04 μM, while the IC<sub>50</sub> of NCTD was 1.87 ± 0.23 μM. This study paves the way for insect-derived agents (CTD) to be applied toward controlling <i>P. americana</i> and contributes to the development of novel insecticides based on PP5 as a target.
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