Ginsenoside Rg1 suppresses urate-induced renal tubular ferroptosis through PPARG-dependent antioxidant signaling.

Hyperuricemic nephropathy (HN) is characterized by renal tubular injury, oxidative stress and interstitial remodeling, but the signaling mechanisms linking urate stress to ferroptotic tubular damage remain incompletely defined. Here, we investigated whether Ginsenoside Rg1 protects against hyperuricemia-associated renal injury by modulating PPARG-dependent ferroptosis signaling. In mice challenged with potassium oxonate and hypoxanthine, Rg1 improved renal histopathology and reduced serum uric acid, creatinine, blood urea nitrogen and xanthine oxidase activity. Rg1 also reversed ferroptosis-associated abnormalities in renal tissue, including glutathione depletion, lipid peroxidation, mitochondrial damage, downregulation of GPX4, SLC7A11 and NRF2, and upregulation of ACSL4. Consistently, in uric acid-exposed HK-2 cells, Rg1 preserved cell viability, restored mitochondrial membrane potential and suppressed oxidative and ferroptotic injury. Network pharmacology prioritized PPARG as a candidate target of Rg1, and molecular docking, molecular dynamics simulation and surface plasmon resonance supported a direct Rg1-PPARG interaction, with an equilibrium dissociation constant of 5.37 μM. Rg1 restored PPARG expression under hyperuricemic stress, whereas pharmacological PPARG inhibition with GW9662 or siRNA-mediated PPARG knockdown abolished Rg1-induced activation of the NRF2/SLC7A11/GPX4 axis and its anti-ferroptotic cytoprotection. These findings identify PPARG-dependent antioxidant signaling as a key mediator of urate-induced tubular ferroptosis and suggest that the Rg1-PPARG axis may be therapeutically exploitable in hyperuricemia-associated kidney injury.