Screening and Identification of Multitarget Uric Acid-Lowering Peptides Derived from Rice Residue Protein and Analysis of Their Mechanisms

This study identified uric acid-lowering peptides from rice residue protein hydrolysates following simulated gastrointestinal digestion. Using ultrafiltration, LC-MS/MS, bioinformatics, and molecular docking, two peptides─FGHPEW (No. 56) and FFAFGR (No. 117)─were screened and validated for their biological activity. Both peptides showed notable <i>in vitro</i> xanthine oxidase (XOD) inhibition (IC₅₀: 476.3 and 673.8 μg/mL, respectively). In zebrafish models of hyperuricemia, they helped restore uric acid balance and improved kidney function. Mechanistically, the peptides inhibited XOD, downregulated <i>Glut9</i>, and upregulated <i>Oat1</i> expression, contributing to enhanced uric acid excretion. Peptide 117 additionally activated <i>Nrf2</i> and showed the potential to inhibit uric acid crystallization. Molecular docking and dynamics simulations confirmed strong, stable binding of both peptides to target receptors via hydrogen bonding and hydrophobic interactions. These results suggest that peptides 56 and 117 lower uric acid through multiple pathways and may serve as promising therapeutic candidates for hyperuricemia.