Regulation of ABC Transporters and Ergosterol Biosynthesis by the Transcription Factor FvADS-1 Controls Azole Resistance and Virulence in Fusarium verticillioides

Fusarium verticillioides is a significant agricultural pathogen and an emerging causative agent of invasive fusariosis in clinical settings. Fusarium species frequently exhibit resistance to available antifungal agents, yet the molecular mechanisms underlying azole resistance remain poorly characterized. In this study, we identified the Zn(II) 2 Cys 6 transcription factor FvADS-1 as a positive regulator of the azole stress response in F. verticillioides . The transcription of FvADS-1 was significantly induced by ketoconazole (KTC), and its deletion increased susceptibility to multiple azole compounds. Mechanistically, FvADS-1 positively regulates the KTC-induced expression of genes encoding ABC transporters and ergosterol biosynthesis enzymes, thereby modulating intracellular KTC accumulation and sterol homeostasis under azole stress. Furthermore, FvADS-1 positively regulates the transcriptional response of peroxisomal genes and contributes to fungal tolerance to oxidative stress. Notably, deletion of FvADS-1 attenuates the virulence of F. verticillioides on maize. The function of ADS-1 is evolutionarily conserved: heterologous expression of N. crassa ads-1 restored azole resistance in FvADS-1 deletion mutant, and the deletion of the F. oxysporum homolog FoADS-1 similarly increased azole susceptibility. Collectively, our study demonstrates that the conserved transcription factor ADS-1 plays a central role in regulating azole resistance and virulence in the pathogen F. verticillioides , offering new insights into antifungal resistance mechanisms in pathogenic filamentous fungi.