17(R)-RvD1 Ameliorates Liver Injury in Hyperuricemia Through Inhibiting Pyroptosis via NF-κB Signaling Pathway

Purpose: The prevalence of hyperuricemia has been increasing worldwide. Most studies have focused on the influences of hyperuricemia on kidney damage and Cardiovascular Disease. However, the impacts of hyperuricemia on the liver remain unclear. 17(R)-RvD1 (Resolvin D1) plays a crucial role in various pathological conditions associated with inflammation. This study aims to investigate the effects of 17(R)-RvD1 on hyperuricemia-induced hepatic injury.

Methods: Potassium oxonate and hypoxanthine were used to establish a hyperuricemic mouse model and investigate the effects of 17(R)-RvD1 on hyperuricemia and concomitant liver injury. Serum uric acid, Xanthine Oxidase (XOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and inflammatory cytokines levels were assessed. Hematoxylin-eosin (HE), Masson and Sirius Red staining were used to detect histological alterations in the liver. The mRNA and protein expression levels were determined by qRT-PCR and Western blot, respectively. Anti-inflammatory and anti-pyroptosis effects of 17(R)-RvD1 were also observed in LO2 cells exposed to uric acid.

Results: 17(R)-RvD1 administration ameliorated serum uric acid, ALT, AST levels; decreased serum IL-1β, IL-6, TNF-α and IL-18 levels; mitigated hepatic inflammatory responses; reduced hepatic NLRP3, ASC and Caspase-1 mRNA expression levels and c-caspase-1, IL-1β and IL-18 levels in hyperuricemic mice. Furthermore, 17(R)-RvD1 administration increased cell viability and reduced LDH release; decreased NLRP3, ASC and Caspase-1 mRNA expression levels and Gasdermin D (GSDMD), c-caspase-1, IL-1β and IL-18 levels in LO2 cells exposed to uric acid. Finally, the anti-pyroptosis effects of 17(R)-RvD1 were blocked when the NF-κB signaling pathway was inhibited by BAY 11-7082.

Conclusion: 17(R)-RvD1 possesses anti-hyperuricemic and anti-inflammatory effects, and the underlying mechanism for ameliorating hepatic injury in hyperuricemia is the inhibition of cell Pyroptosis via downregulating the NF-κB signaling pathway. 17(R)-RvD1 could serve as an ideal candidate drug and increase options for the treatment of hyperuricemia.

17(R)-RvD1; NF-κB; hyperuricemia; liver injury; pyroptosis.