Sterol Remodeling in Fusarium oxysporum Drives Mammalian Virulence through Pyroptosis and Chemokine Suppression

Members of the Fusarium oxysporum species complex are globally distributed soil fungi and plant pathogens that increasingly cause severe and often treatment-refractory human infections. Because clinical and non-clinical isolates arise from overlapping ecological reservoirs, the biological features that contribute to enhanced virulence in mammalian hosts remain incompletely defined. Here, we identify remodeling of ergosterol homeostasis as a distinguishing characteristic of clinically derived isolates, which displayed increased ergosterol biosynthetic activity, elevated extracellular ergosterol release, reduced azole accumulation, and increased pathogenicity in a murine infection model. Functionally, heightened sterol flux promoted caspase-1–dependent macrophage pyroptosis while selectively suppressing chemokine production through IL-10/TGF-β–associated pathways, resulting in impaired neutrophil recruitment despite robust proinflammatory cytokine induction. We propose that enhanced sterol biosynthesis, potentially favored under azole exposure, amplifies pathogenic potential in mammalian hosts. These findings redefine ergosterol as an immunomodulatory virulence determinant linking sterol metabolism, host adaptation, and disease severity.