Hyperuricemia (HUA) is the second most common metabolic disease nowadays, and is characterized by permanently increased concentrations of serum uric acid. In this study, two novel hexapeptides (GPAGPR and GPSGRP) were identified from Apostichopus japonicus hydrolysate and predicted to have xanthine oxidase (XOD) inhibitory activity by molecular docking. Their in vitro XOD inhibition rates reached 37.3% and 48.6%, respectively, at a concentration of 40 mg mL^-1. Subsequently, in vivo experiments were carried out in a HUA mouse model, and we found that both peptides reduced the serum uric acid by inhibiting uric acid biosynthesis and reabsorption, as well as alleviated renal inflammation via suppressing the activation of the NLRP3 inflammasome. 16S rDNA sequencing indicated that both peptide treatments reduced the richness and diversity of the gut microbiota, altered the composition in the phylum and genus levels, but different change trends were observed in the phylum Verrucomicrobia and genera Akkermansia, Dubosiella, Alloprevotella, Clostridium unclassified and Alistipes. In addition, changes in the renal microRNA (miRNA) profiles induced by GPSGRP treatment were analyzed; 21 differentially expressed (DE) miRNAs were identified among groups, and KEGG pathway analysis indicated that their potential target genes were involved in pluripotency of stem cell regulation, mTOR signaling pathway and proteoglycans. Moreover, ten miRNAs involved in the HUA onset and alleviation were identified, which showed a high correlation with genera related to the metabolism of short-chain fatty acids, bile acids and tryptophan. This study delineated two hexapeptides as potential microbiota modulators and miRNA regulators that can ameliorate HUA.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	18
2	Biochemistry	1	1	18
3	Pharmacology	1	1	18
4	Oxidative Stress	1	1	18
5	Bioanalysis	1	1	18

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