NLRP3 x URAT1

Hyperuricemia and monosodium urate induced nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation is the major pathogenesis for gouty arthritis, and urate transporter 1 (URAT1) is a proven target for hyperuricemia. In this study, scaffold hopping modification with tranilast led to the identification of HNW005, an NLRP3 inflammasome and URAT1 dual-target inhibitor, which exhibited notable inhibitory potency against NLRP3 inflammasome activation (K_D = 204.6 nM, IC₅₀ = 1.7 μM) and uric acid transmembrane transportation (IC₅₀ = 6.4 μM). Importantly, HNW005 displayed significant in vivo efficacy with respect to anti-inflammatory, analgesic, and uric acid-lowering effects (decreasing rate = 64.8 % at 2 mg/kg). In addition, HNW005 also displayed an acceptable pharmacokinetic profile (F = 41.37 %, t_1/2 = 3.07 h). Collectively, the results showed that developing dual-target inhibitors of NLRP3 inflammasomes and URAT1 is a feasible strategy for the treatment of gouty arthritis, and HNW005 is worthy of further investigation.

Benincasae Exocarpium (BE) is the outer peel of the herbaceous plant Benincasa hispida Cogn., belonging to the Cucurbitaceae family. BE has a long-standing history in medicinal applications for its capabilities to relieve thirst, promote diuresis, eliminate dampness, and clear heart fire, which suggest its potential for the intervention of hyperuricemia (HUA).

This study aimed to clarify how BE exerts its anti-HUA effect in HUA rats, especially its protective function on liver and kidney damage.

UPLC-MS/MS analysis was employed to identify the components of BE, HUA rats were established by potassium oxonate and hypoxanthine, and the biochemical parameters and transcriptomics analyses of liver and kidney in BE-treated HUA rats were carried out with further verification by Western Blot.

BE mainly consisted of amino acids, flavonoids, alkaloids, and terpenoids with a moderate inhibitory effect on xanthine oxidase (XOD, IC₅₀ = 720.6 μg/mL) in vitro and reduced serum levels of uric acid (UA), TC, TG, IL-1β, IL-6 and TNF-α, as well as lowered AST, CRE, and BUN levels in vivo, which supported the efficacy of BE in improving liver and kidney function in HUA rats. In addition, BE inhibited UA synthesis and facilitated UA excretion by regulating the expressions of XOD in liver and URAT1, GLUT9, ABCG2 and OAT1 in kidney. Moreover, BE regulated HUA-induced renal inflammation and glomerular swelling through TLR4/NF-κB/NLRP3 signaling pathway, as evidenced by validation experiments combining transcriptomics with Western Blot analysis. Notably, liver transcriptome analysis and further molecular data indicated that BE alleviated metabolic disorders caused by HUA through regulation of IRS2/FoxO1/AMPK/ACC signaling pathway.

Above results suggest that BE primarily promotes UA excretion and is effective in both reducing UA reabsorption and inhibiting UA production. Notably, BE exerts protective effect on liver and kidney of HUA rats by reducing glomerular swelling and alleviating hepatic metabolic disorders. Therefore, BE can act as a dietary supplement with anti-HUA property.

Hyperuricemia (HUA) is a chronic disease caused by abnormal purine metabolism with high prevalence. Dihydromyricetin (DMY) is a natural flavonoid that is abundant in plants, such as vine tea, grapes and bayberry. DMY has been shown to possess multiple biological properties, but its anti‐HUA effect remains underexplored. In the present study, the regulatory effects of DMY on HUA and its complications and mechanism were investigated.

DMY (10 and 20 μmol L−1) treatment significantly reduced xanthine oxidase (XOD) expression and uric acid (UA) synthesis in normal human liver cell strain cells, and intraperitoneal administration of DMY (100 mg kg−1) also significantly reduced serum UA and the expression of hepatic XOD in HUA mice. After DMY treatment for 12 consecutive days, the uricosuric protein, ATP‐binding cassette subfamily G member 2, was upregulated, and reabsorption proteins, including urate transporter 1 and glucose transporter 9, were downregulated, which was consistent with the results of monosodium urate‐induced HUA in human renal tubular epithelial cell line and human colon adenocarcinoma cell line cell models. In addition, DMY significantly ameliorated HUA‐induced renal injury, and foot edema induced by monosodium urate. The nucleotide‐binding oligomerization domain‐like receptor family containing pyrin domain 3 (NLRP3) inflammasome was activated in HUA mice as evidenced by upregulation of NLRP3, caspase‐1, ACS, TNF‐α and IL‐1β in the kidney and foot, which was significantly suppressed by DMY treatment.

Collectively, these findings suggested that DMY may play important roles in experimental HUA. © 2025 Society of Chemical Industry.