Alleviation of senkyunolide A on hyperuricemia and hyperuricemia-induced renal damage in rats.

Senkyunolide A (SEA), the major phthalide from the ethyl acetate extract of traditional Chinese medicine Chuanxiong (Ligusticum chuanxiong), potently inhibited xanthine oxidase (XOD) in vitro in our preliminary study. However, its efficacy in alleviating hyperuricemia and hyperuricemia-induced renal injury in vivo, along with its molecular mechanisms, remains unverified. The study found that SEA significantly lowered serum uric acid levels and attenuated hyperuricemia-induced renal damage of rats, while exhibiting no hepatotoxicity. Further mechanism study suggested that SEA inhibited the production of uric acid by inhibiting XOD. Moreover, SEA significantly promoted uric acid excretion. Western blotting results suggested that SEA increased protein expression of ABCG2 and decreased expression levels of GLUT9 and URAT1 in the kidneys. Transcriptomic, qRT-PCR and ELISA data revealed that SEA alleviated HUA-induced kidney inflammation of rats, which was associated with IL-17 and TNF signaling pathways. SEA significantly downregulated the mRNA expression levels of Nfkb1, Tnfrsf1a, IL-1β, IL-6, Jun, Cxcl1, Fos and S100a9. Simultaneously, SEA reduced the mRNA expression levels and inhibited the activities of caspase-3, caspase-8, and caspase-9 in the kidneys of HUA rats, indicating that SEA alleviated HUA-induced renal apoptosis. Overall, SEA exhibited excellent potential as a treatment for hyperuricemia with a favorable safety profile. This study firstly reports SEA as a candidate drug for hyperuricemia.