Multi-strategy profiling identifies limonin's dual role in gout: restoring uric acid homeostasis and suppressing inflammatory response

Abstract

Gout is an increasingly prevalent global health issue, characterized by disrupted uric acid (UA) homeostasis, and commonly accompanied by hepatorenal damage and inflammation. This study investigated the effects of limonin on tissue pathology, UA regulation, and inflammation in a gout rat model. Histopathological analysis revealed that limonin significantly alleviated damage in the ankle joints, livers and kidneys. Limonin restored UA balance by enhancing renal UA excretion via transporter modulation and reducing UA production through inhibition of hepatic xanthine oxidase. Urine metabolomic analysis further confirmed that limonin modulates purine and pyrimidine metabolic pathways involved in UA regulation. Transcriptomic analysis of hepatorenal tissues, supported by western blotting, molecular docking, and CETSA, revealed that limonin bound to AMPK and then inhibited NF-κB signaling, thus exhibiting anti-inflammatory and UA-lowering effects. These findings showed limonin's dual role in UA regulation and inflammation inhibition, highlighting its potential as a functional food ingredient for gout management.