Induced cuproptosis by targeting the ESCRT-III complex potentiates copper-based control of smut diseases.

Sporisorium scitamineum, the fungal pathogen causing sugarcane smut, employs a unique copper detoxification mechanism to evade cuproptosis, a copper-dependent cell death pathway recently highlighted in anticancer research. This study reveals its copper tolerance through a novel cuproptosis evasion strategy. Through fluorescence tracing of the SsCtr3 transporter and copper ions combined with elesclomol induction, we found that the ESCRT pathway mediates SsCtr3 to sequester excess copper into vacuoles under high‑copper stress. This sequestration prevents cytoplasmic copper overload and subsequent mitochondrial DLAT aggregation that triggers cuproptosis. Pathogenicity assays revealed that disrupting the ESCRT pathway significantly enhances efficacy of copper-based compounds treatments. By elucidating the molecular crosstalk between fungal copper transport and cuproptosis suppression, this study delineates the fungus's copper homeostasis-cuproptosis axis, providing a strategic framework for optimizing copper-based disease control in sugarcane and related crops.