Dual-pathway mechanism of vanadium-induced hepatotoxicity in ducks: Synergistic crosstalk between glucose homeostasis disruption and NADH/FSP1/COQ10 axis-driven ferroptosis.

In intensive duck production systems, vanadium (V) is widely used as a growth-promoting additive, but excessive supplementation poses health risks to ducks. Previous research indicated that V could cause damage to organs by disrupting the structure and function of mitochondria and the endoplasmic reticulum. However, the precise mechanism of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in V-induced hepatotoxicity remains unclear. To fill this gap, this study employed network toxicology to analyze the hepatotoxicity of V, and further validated the pivotal roles of glucose homeostasis and ferroptosis in this process through targeted MAMs proteomics. The results indicated that V exposure increased liver dysfunction markers, disrupted hepatic cord structure, and widened ER-mitochondria gaps. Besides, V exposure up-regulated the levels of the IP3R-Grp75-VDAC1 complex in MAMs while promoting its dissociation. Moreover, the sequencing results of MAMs demonstrated that V primarily induced hepatotoxicity by disturbing the glycolysis/gluconeogenesis pathway. Notably, V exposure exacerbated lipid peroxides and Fe2+ accumulation while inhibiting the NADH/FSP1/CoQ10 axis, down-regulating the expression levels of ferroptosis-related factors in livers. These findings demonstrated that dietary V overexposure impaired hepatic MAMs integrity, disrupted glucose homeostasis, and suppressed the NADH/FSP1/CoQ10 axis, which ultimately induced ferroptosis-mediated liver injury in ducks.