Cafestol alleviated hyperuricemia by inhibiting uric acid synthesis through the regulation of PPARγ/PPARα/XOD pathway

• Network pharmacology combining molecular docking analysis suggests that cafestol may alleviate hyperuricemia (HUA) through interaction with PPARγ. • In human hepatocyte HepG2 cells, cafestol activated PPARγ, enhanced the formation of the PPARγ–RXRα heterodimer and suppressed PPARα-mediated XOD expression, leading to reduced endogenous uric acid (UA) synthesis. • In HUA mice, cafestol alleviated HUA by activating PPARγ to decrease endogenous UA production. It also inhibited liver injury, improved cholesterol metabolism and kidney function, as well as promoted urinary UA excretion. Cafestol, a natural diterpenoid found in coffee, exhibits various bioactive properties, such as regulation of lipid metabolism, antioxidant activity, and anti-inflammation. Nevertheless, its potential role in managing hyperuricemia (HUA) has not been well studied. This study aimed to investigate the beneficial effects of cafestol on HUA and to clarify its underlying molecular mechanism. Potential targets of cafestol were predicted using network pharmacology and molecular docking. Its effects on uric acid (UA) production were further verified in vitro and in vivo . Integrated analyses identified peroxisome proliferator-activated receptor gamma (PPARγ) as a key target of cafestol. In human hepatocytes HepG2, cafestol upregulated PPARγ expression, promoted its heterodimer formation with retinoid X receptor alpha (RXRα), and suppressed UA synthesis along with the expression of PPARα and xanthine oxidase (XOD). Knockdown of PPARγ abolished the reduction in UA and the downregulation of PPARα and XOD by cafestol, whereas PPARα knockdown had no effect on PPARγ expression but still decreased UA production. In a mouse model of HUA, cafestol significantly reduced serum levels of UA, AST, ALT, total cholesterol, and LDL-cholesterol, while increasing HDL-cholesterol. It also elevated 24-h urine volume and urinary UA excretion and improved kidney function. Moreover, cafestol activated hepatic PPARγ, enhanced PPARγ–RXRα heterodimerization, and suppressed PPARα/XOD expression in HUA mice. This study demonstrates that cafestol alleviates HUA by activating PPARγ, which subsequently decreases UA production through inhibiting PPARα-mediated XOD expression. These results highlight the potential of cafestol as a promising functional food component for the prevention or management of HUA.