Screening and Mechanistic Insights of Antidepressant Walnut Protein Hydrolysates: IDO1 Inhibition and Tryptophan Metabolism Optimization

The neuroprotective effects of walnut protein hydrolysates (WPH) have been widely reported, and its antidepressant potential is worthing to exploring. In this study, a series of WPH were prepared by several group of complex hydrolysis and screened for potential antidepressant activity. The results showed that the hydrolyzed product (G2) from alkaline protease and pepsin had the most antidepressant potential. This is because G2 has anti-inflammatory effects and has a strong inhibitory effect on indoleamine 2,3-dioxygenase 1 (IDO1) activity at the chemical and cellular level, with a chemical IC₅₀ at 70.26 μg/mL and a cellular IC₅₀ at 65.29 μg/mL. G2 significantly improved chronic unpredictable mild stress (CUMS)-induced depressive behavior in mice. Trp targeted metabolomics analysis revealed that G2 reversed the CUMS-induced conversion of excess Trp to kynurenine (Kyn) and alleviated the Trp metabolic imbalance by inhibiting IDO1 activity. These findings suggest G2 alleviates depressive symptoms by inhibiting IDO1 and optimizing Trp metabolism, indicating its potential as a natural antidepressant functional food.