Febuxostat alleviates gout-associated hyperuricemia and inflammation by downregulating IL1A to modulate TLR2/TLR4/NF-κB signaling pathway.

BACKGROUND

Gout, a prevalent inflammatory condition that results in inflammation and hyperuricemia, is brought on by the buildup of monosodium urate (MSU) crystals. Febuxostat (Feb), a xanthine oxidase inhibitor, helps control hyperuricemia, although further study is required to understand how it lowers inflammation.

METHODS

Feb or allopurinol (ALP) was added after Human Kidney-2 (HK-2) cells were treated with MSU to induce inflammation and hyperuricemia. We assessed inflammatory markers, Uric acid (UA) levels, and cell viability using Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). Differentially expressed genes (DEGs) and enriched pathways were found using RNA sequencing (RNA-Seq). IL1A was discovered to be a hub gene, and its role in regulating the TLR2/TLR4/NF-κB signaling pathway was further explored through overexpression experiments.

RESULTS

Feb alleviated MSU-induced cytotoxicity. Both Feb and ALP inhibited the upregulation of xanthine dehydrogenas/xanthine oxidase (XDH/XOD), UA levels, and UA transporters (URAT1 and GLUT9) induced by MSU, with Feb having a more pronounced effect. MSU markedly raised IL-1β, IL-6, TNF-α, and IL-18 levels, which were reduced by Feb or ALP. RNA-Seq showed that IL1A was significantly downregulated after Feb treatment and enriched in the TLR4 signaling pathway. Feb inhibited IL1A expression and attenuated the TLR2/TLR4/NF-κB pathway, while IL1A overexpression reversed these effects and restored UA levels, transporter expression, and cytokine production.

CONCLUSION

Feb treats gout by downregulating IL1A to modulate the TLR2/TLR4/NF-κB signaling pathway, making IL1A a potential biomarker for gout management and highlighting the therapeutic prospects of Feb in targeting inflammation-related pathways.