Lycopene mitigates T-2 toxin-induced hepatic ferroptosis by targeting the Nrf2/mitophagy axis in mice.

T-2 toxin is a typical mycotoxin that seriously threatens human and animal health. Liver is the major target organ of T-2 toxin. To elucidate the precise hepatotoxicity mechanism and discover a natural antagonist of T-2 toxin. T-2 toxin (0, 0.5, 1, 2 mg/kg BW)-induced liver injury model, Ferrostatin-1 (1 mg/kg·BW) interference model, Parkin-/- mice model, Nrf2-activating model (tBHQ, 20 mg/kg·BW) and lycopene (5 mg/kg·BW) treatment model were constructed. Proteomics revealed that ferroptosis is a critical hepatotoxicity mechanism of T-2 toxin. Blocking ferroptosis alleviated the liver damage and mitophagy under T-2 toxin threat. However, these processes were exacerbated in Parkin-/- mice. In vivo mouse model confirmed that Nrf2 activation increased PINK-Parkin mediated mitophagy and alleviated T-2 toxin-induced ferroptosis, suggesting that Nrf2/mitophagy axis was involved in T-2 toxin-induced hepatic ferroptosis. Further analysis revealed that lycopene promoted Nrf2 nuclear translocation and PINK-Parkin mediated mitophagy to mitigate T-2 toxin-induced hepatic ferroptosis.