Insect-specific aldehyde synthase governs cuticle strength: a selective insecticide target

Cuticular sclerotization is crucial for insect adaptation and flight, historically thought to be dominantly driven by dopamine and its downstream products. In this study, we demonstrate that 3,4-dihydroxyphenylacetaldehyde (DHPAA)—produced by DHPAA synthase (DHPAAS) and known in humans as a toxic dopamine metabolite—plays a central role. Cross-species RNAi, mechanical testing, and precursor quantification, consistently support this conclusion. In the migratory locust, we further reveal that DHPAA is essential for cuticular mechanical properties, whereas dopamine primarily regulates pigmentation. These findings establish a new paradigm for the chemistry of insect cuticle sclerotization. Then, we elucidate the catalytic mechanism of DHPAAS, laying the groundwork for its application in biosynthesis. Furthermore, we identify 2,5,2′,4′-tetrahydroxychalcone as a selective inhibitor of DHPAAS. Given that DHPAAS is insect-specific and absent in non-insect arthropods and vertebrates, our work points to a promising strategy for developing selective insecticides.