NKT (5 mg/kg) co-treatment remarkably ameliorates D-GalN-induced anxiety- and depression-like behaviours. NKT could ↑ serum alanine transaminase and aspartate transaminase levels, alleviate hyperammonaemia-induced OS by activating Keap1/Nrf2/HO-1 antioxidant pathways, ↓ the expression of inducible NOs and NOX2 in Hippoc and prefrontal cortex, ↑ the vitality of SOD, ↑ catalase and GSH levels in serum, liver, and brain, and significantly ↓ the generation of MDA. NKT also ↓ the level of ammonia in serum and brain and ↑ the activity of glutamine synthase in the Hippoc and prefrontal cortex. Here, NFE2L2 is linked to major depressive disorder.