Ginsenoside Rg3 attenuates hyperuricemia-associated AKI by upregulating CPT1A and suppressing...

Hyperuricemia-associated acute kidney injury (HUA-AKI), a frequent complication of chronic hyperuricemia, is driven by oxidative stress, inflammation, and pyroptosis in renal tubular epithelial cells. Ginsenoside Rg3, a principal bioactive compound derived from Panax ginseng, possesses anti-inflammatory and metabolic regulatory activities; however, its therapeutic effects and underlying mechanisms in HUA-AKI remain elusive. In this study, an HUA-AKI mouse model was established via intraperitoneal injection of potassium oxonate combined with oral hypoxanthine, and an in vitro model using uric acid (UA)-stimulated HK-2 cells. Rg3 treatment markedly improved renal function, reduced tubular injury, and alleviated oxidative stress without altering serum UA levels. Transcriptomic profiling identified 229 differentially expressed genes (DEGs) reversed by Rg3, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed significant inhibition of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and pyroptosis pathways, alongside upregulation of the carnitine palmitoyltransferase 1A (CPT1A)-mediated fatty acid oxidation pathway. Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) confirmed that Rg3 upregulated CPT1A expression and suppressed activation of NLRP3, cleaved caspase‑1, gasdermin D N‑terminal fragment (GSDMD‑NT), as well as the release of interleukin (IL)-1β and IL-18 in both mouse kidney tissues and HK-2 cells. Notably, co-administration of the CPT1A inhibitor sodium taurocholate (STC) partially abolished the renoprotective effects of Rg3, as demonstrated by restored cell viability, elevated lactate dehydrogenase (LDH) release, re‑elevation of pyroptosis-related proteins and cytokines, and reappearance of membrane pore formation and rupture under transmission electron microscopy. Collectively, our findings suggest that Rg3 may ameliorate HUA‑AKI, at least in part, through CPT1A upregulation and subsequent suppression of the NLRP3/caspase-1/GSDMD axis, positioning Rg3 as a promising therapeutic candidate for HUA-AKI.