Mechanisms and preliminary validation of luteolin in the treatment of hyperuricemia based on network pharmacology and toxicology studies

Abstract

Hyperuricemia (HUA) refers to a condition where fasting serum uric acid levels exceed 420 μmol/L in men and 350 μmol/L in women, affecting 17.4% of China’s general population, showing increasing prevalence among younger individuals. Luteolin, a common flavonoid compound, exhibits multiple biological effects, including inhibition of tumor proliferation and inflammatory responses. It also suppresses the activity of urate transporter 1 (URAT1), promoting uric acid excretion. This study is the first to integrate network toxicology and network pharmacology approaches to systematically analyze the multi-target mechanisms of adenine-induced HUA and luteolin-treated HUA, with molecular docking validation of interaction targets. We constructed compound-pathway-intersection gene networks and a dual-group PPI network to analyze the mechanisms of adenine-induced HUA and luteolin-treated HUA. The dual-group PPI network identified 7 shared targets, namely XDH, PYGL, IL10, PPARG, TNF, VEGFA, and MAOA, involving core intersecting pathways such as purine-xanthine metabolism and insulin resistance. Luteolin may activate PPARG to regulate inflammation and uric acid excretion modules in the adenine network. GO-KEGG analysis indicates that intersection genes for adenine pathogenesis involve diverse biological processes, cellular components, and molecular functions, with core target KEGG analysis revealing 15 signaling pathways. Luteolin’s therapeutic targets are associated with more entries, and its core target KEGG analysis identified 46 signaling pathways. Molecular docking shows TNF, PPARG, and PYGL bind to both luteolin and adenine with negative binding energies, and luteolin’s binding energies are all below 5 kJ/mol, confirming stable binding. Luteolin’s anti-HUA mechanism is characterized by inhibition of production, promotion of excretion, anti-inflammation and metabolic regulation, but interactions with gut microbiota metabolites require further study.

Keywords

hyperuricemia (HUA) / luteolin / network pharmacology / network toxicology / molecular docking

Acknowledgments

This work was financially supported by the National College Student Innovation and Entrepreneurship Project.

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