Nano-selenium suppresses cuproptosis to restore mitophagic flux and alleviate deoxynivalenol-induced renal inflammation

Nano-Se alleviates DON-induced cuproptosis in chicken kidney. • Nano-Se mitigates DON-induced mitochondrial oxidative damage by suppressing cuproptosis. • Nano-Se prevents DON-induced lysosomal membrane permeabilization and mitophagic flux blockage by inhibiting mitochondrial oxidative damage. • Nano-Se attenuates DON-evoked renal inflammation by restoring mitophagic flux. Deoxynivalenol (DON) is a widespread mycotoxin contaminating cereal grains and animal feed, posing significant risks to livestock health and food safety. However, the molecular mechanisms underlying DON-induced nephrotoxicity remain poorly understood. In this study, we identify cuproptosis as a critical driver of DON-induced nephrotoxicity in chickens and investigate the protective role of nano-selenium (Nano-Se). DON exposure disrupted copper homeostasis and induced cuproptosis, as evidenced by dysregulation of FDX1, LIAS, and DLAT, resulting in mitochondrial oxidative damage and electron transport chain (ETC) dysfunction. Excessive mitochondrial reactive oxygen species (mtROS) further impaired lysosomal acidification, resulting in lysosomal membrane permeabilization (LMP) and blockade of mitophagic flux, ultimately triggering a robust inflammatory response. Nano-Se supplementation effectively mitigated DON-induced renal injury by suppressing cuproptosis, restoring mitochondrial redox balance, preserving ETC function, rescuing lysosomal function, re-establishing mitophagic flux, and attenuating inflammatory responses in vivo and in vitro. Mechanistically, pharmacological modulation targeting copper levels, mtROS generation, or mitophagic flux abolished the protective effects of Nano-Se. Collectively, these findings reveal that DON induces nephrotoxicity via the cuproptosis-mtROS-mitophagy axis and that Nano-Se ameliorates DON-induced renal inflammation by suppressing cuproptosis, reducing mtROS accumulation, and restoring mitophagic flux. This study provides a mechanistic basis for the use of Nano-Se as a potential therapeutic agent against mycotoxin-associated renal injury, with implications for environmental health risk assessment and livestock production. Download: Download high-res image (182KB) Download: Download full-size image