Gambogic Acid Inhibits MDCK Cyst Enlargement by Suppressing Inflammation via p38 and NF-κB Pathway Inhibition

Interstitial inflammation is a major component of polycystic kidney disease (PKD) pathophysiology, driving renal cystogenesis progression. Gambogic acid (GA), a xanthone compound, exhibits antiproliferative, anti-inflammatory, and anticancer effects. GA inhibits <i>in vitro</i> renal cyst progression by inhibiting the cell proliferation pathway. However, its effect on cellular inflammation in PKD remains unclear. This study aimed to elucidate the detailed mechanisms by which GA inhibits inflammatory pathways to slow cyst growth in an <i>in vitro</i> PKD model. GA at 0.5-2.5 μM significantly retarded Madin-Darby canine kidney (MDCK) cyst growth in a dose-dependent manner. Real-time RT-PCR revealed that GA (2.5 μM) suppressed IL-6 and TNF-α mRNA expression. Notably, GA strongly inhibited p38 and p65NF-κB phosphorylation in both dose- and time-dependent manners in MDCK and <i>Pkd1</i> mutant cells. Collectively, these findings suggest that GA may retard MDCK cyst enlargement partly by inhibiting inflammation pathways. GA may represent a promising plant-based drug candidate for treating autosomal dominant polycystic kidney disease.