Unraveling the Mechanism of Perillyl Alcohol and Its Derivatives as Potent Antifungal Agents against Gray Mold

Fungicides are often limited by poor efficacy and high toxicity. Our previous research identified perillyl alcohol (POH) as a promising plant-derived fungicide. Here, POH exhibits antifungal activity by inducing metacaspase-independent apoptosis in Botrytis cinerea. Furthermore, POH triggers both nonselective and selective autophagy, particularly endoplasmic reticulum autophagy (ER-phagy) and mitochondrial autophagy (mitophagy). Ubiquitylation analysis revealed that POH promotes protein ubiquitination. Additionally, transcriptome analysis revealed the suppression of Na/K-ATPase-related gene expression and activity. Importantly, we identified BcBet4 as a direct molecular target of POH, with binding interactions contributing to its mode of action. Through systematic chemical modifications, we developed POH-10, a derivative exhibiting enhanced antifungal efficacy and a stronger binding affinity to BcBet4. These findings provide valuable insights for the development of novel antifungal agents. As a multitarget fungicide, POH holds significant potential for economically and ecologically sustainable crop disease management.