β-Caryophyllene oxide inhibits lysine acetylation of histones in Fusarium proliferatum to block ribosomal biosynthesis and function

The natural bicyclic sesquiterpene, β-Caryophyllene oxide (BCPO), has demonstrated inhibitory activity against Fusarium species. While previous studies have documented its antifungal properties through various biochemical mechanisms, the role of BCPO in modulating epigenetic modifications of DNA via histone deacetylases (HDACs) has received comparatively less attention. The study aims to elucidate how BCPO inhibits Fusarium proliferatum by affecting histone acetylation. Our results indicate that BCPO enhances FPRO_01165 (FpSIR2) enzyme activity to 6.01 ng/min/mg, representing a 55.30 % increase. Molecular docking analysis and molecular dynamics simulation confirmed the interaction between BCPO and FpSIR2. Furthermore, high concentrations (HC) of BCPO significantly inhibited the growth of F. proliferatum, resulting in marked reductions in H3K9ac and H3K27ac modification levels. We conducted chromatin immunoprecipitation sequencing (ChIP-seq) to identify enrichments of H3K9ac and H3K27ac, while also obtaining transcriptomic data from the HC treatment group. Combined analyses revealed that decreased levels of H3K9ac and H3K27ac primarily affected ribosomal pathways in F. proliferatum, leading to downregulation of several ribosomal genes and their corresponding proteins, such as RPL4, RPS19, and RPS16. Our findings suggest that BCPO stimulates both the production and activity of FpSIR2, which subsequently inhibits histone lysine acetylation in F. proliferatum. This inhibition suppresses ribosome biosynthesis and function as well as overall growth in this pathogen. The property of BCPO to reduce acetylation provides new insights for developing highly efficient yet low-toxicity antifungal agents.