In recent years, deltamethrin (DEL) pollution poses a significant threat to aquaculture; however, the protective role of vitamin C (VC) against acute toxicity in crucian carp has not been well understood. This study provides compelling evidence that exposure to 2.0 mg/L waterborne VC significantly mitigates DEL-induced 96-hour mortality in crucian carp (p < 0.001). Importantly, this research represents the first documentation of the protective effects of waterborne VC in fish, which is mediated through the modulation of the aryl hydrocarbon receptor (AhR)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway—a mechanism not previously reported in crucian carp. The observed protective effect is attributed to the enhancement of antioxidant and anti-inflammatory responses via this signaling pathway. Exposure to DEL at 6.2 μg/L resulted in severe oxidative stress, characterized by significantly increased malondialdehyde (MDA) levels and depletion of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) in the liver and intestine (p < 0.01). Histopathological damage, including hepatic vacuolation, shortened villi, and inflammation, as well as elevated reactive oxygen species (ROS), was observed. Co-exposure to VC normalized antioxidant markers, reduced MDA and ROS levels, and alleviated tissue damage (p < 0.05). Mechanistically, VC counteracted the suppression of AhR/Nrf2 by DEL, leading to the statistically significant upregulation of antioxidant genes (gst, sod, cat) and suppression of pro-inflammatory cytokines (il1β, il6, tnfα) (p < 0.05). VC exhibited tissue-specific regulation by enhancing hepatic Nrf2 defenses and co-activating intestinal AhR/Nrf2, as confirmed by Western blot analysis. Our study shows that waterborne VC effectively protects against acute DEL toxicity under current experimental conditions, suggesting its potential as an eco-friendly emergency intervention in aquaculture during sudden pesticide exposure. Further research is needed to confirm its effectiveness in complex pond systems and various fish species.
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