UA mitigates cisplatin-induced toxicity suggesting involvement of the KEAP1-NRF2 pathway: insights from...

Cisplatin is a widely used chemotherapeutic agent known for its potent antitumor activity, however its clinical use is significantly limited by dose-dependent multiorgan toxicity predominantly affecting the kidney, heart and reproductive organs, with mechanisms involving oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this study the potential protective effects of ursolic acid (UA), a pentacyclic triterpenoid with known antioxidant and antiapoptotic properties, against cisplatin-induced organ toxicity was explored. Thirty Swiss albino mice were randomly divided into five groups including control, cisplatin-treated, cisplatin + low-dose UA, cisplatin + high-dose UA and UA alone, with cisplatin (10 mg/kg, i.p.) given as a single dose and UA administered daily for 14 days, and kidney, heart and testis tissues were examined histologically showing that cisplatin caused glomerular and tubular degeneration, myocardial disarray with inflammatory infiltration and degeneration of seminiferous tubules, while UA co-administration significantly reduced these histopathological alterations in a dose-dependent manner, and serum reactive oxygen species (ROS) levels confirmed its antioxidant potential, and further molecular docking followed by 200 ns molecular dynamic simulations in GROMACS targeting the KEAP1-NRF2 complex (PDB ID: 2FLU) showed strong binding of UA (-7.2 kcal/mol), comparable to curcumin supporting a possible role in NRF2 activation, and simulation analysis demonstrated that both UA-KEAP1 and curcumin-KEAP1 complexes formed stable interactions with UA exhibiting slightly lower RMSD fluctuations and consistent radius of gyration values indicating a compact and dynamically stable complex, suggesting that UA may offer protection against cisplatin-induced toxicity by modulating oxidative stress and the KEAP1-NRF2 pathway.