Myo-inositol metabolism counteracts mycotoxin hijacking and confers broad resistance to fungal diseases in crops.

Fusarium pathogens deploy mycotoxins as virulence factors to promote disease progression in cereal crops, leading to yield loss and food contamination. However, how mycotoxins interact with crops remains unknown. Here, we discover that mycotoxin deoxynivalenol (DON) hijacks multiple wheat nicotinamide adenine dinucleotide (NAD)+-dependent metabolic enzymes, disrupting glycolytic and TCA-cycle homeostasis, thereby contributing to Fusarium head blight (FHB) susceptibility. In this context, we identify that myo-inositol-1-phosphate synthase (MIPS), one DON interactor, redirects myo-inositol-phosphoinositide metabolism, promoting DON transport into vacuoles in a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent manner. This sequestration counteracts DON's cytoplasmic hijacking, preventing host central metabolic disruption and FHB development. Increasing MIPS expression in wheat and maize confers broad resistance to Fusarium diseases without agronomic penalty in field trials, rescuing up to 43% yield loss and reducing up to 88% DON accumulation in grain. Our findings reveal a metabolic "hijacking-counteracting" framework in plant-mycotoxin interactions, providing a robust strategy for improving crop disease resistance and mycotoxin management.