Nematodes exposed to furfural acetone exhibit a species-specific vacuolar H⁺-ATPase response

Furfural acetone (FAc) is widely used as an additive by the food industry, as well as an intermediate in several fine chemical industries. Its nematicidal activity against the free-living model organism Caenorhabditis elegans and the parasitic nematode Meloidogyne incognita are well known, but its molecular mechanism of action remains unclear. To deep this subject, we performed 48-h lethal tests on eight nematode species, encompassing free-living, plant-parasitic, and animal-parasitic nematodes. Our results revealed that FAc possesses broad-spectrum nematicidal activity, with potent effects against parasitic nematodes such as Strongyloides stercoralis and M. incognita. In contrast, it exhibited weak activity against the free-living nematode C. elegans, suggesting its potential as a selective nematicide. Our investigation unveiled that FAc binds to the vacuolar H⁺-ATPase subunits VHA-12 and VHA-13, accelerating intestinal cell necrosis and leading to the death of C. elegans. It is the first discovery that VHA-12 and VHA-13 can serve as target proteins for triggering nematode cell necrosis. The interaction results indicated that FAc targets proteins VHA-12 and VHA-13 of different nematodes and confers broad-spectrum nematicidal activity. And the Spearman analysis results illustrated that the differential nematicidal activity of FAc against various nematodes is attributed to variations in the sequence and structure of the receptor proteins VHA-12 and VHA-13 among different nematode species. Our results illuminate the molecular mechanism underlying the differential toxicity of FAc to different nematodes, and provide valuable data for the comprehensive risk assessment of FAc release into the environment.