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Background: Moonseed vine (Triclisia gilletii Staner) a member of the Menispermaceae family, has been previously investigated and reported in our laboratory to exhibit antilithiatic potentials against ethane-1,2-diol induced nephrolithiasis. However, the mechanism underlying its action is not clear. Purpose: Mechanism of action of aqueous methanolic leaf extact of Triclisia gilletii (TGAMLE 100 mg/kg) in comparison with compounds identified in TGAMLE (Quercetin (20 mg/kg), oleanolic acid (10 mg/kg), stigmasterol (20 mg/kg), and sitosterol (20 mg/kg)) was investigated against ethane-1,2-diol administered rats. Methods: The mRNA expression of antioxidant marker genes (nuclear factor erythroid- 2 – related factor- 2 (NRF2) and Heme oxygenase-1 (HO-1)) and crystal binding genes (CD44 and osteopontin (OPN)) were assessed using RT-PCR. Results: Ethane-1,2-diol administration down-regulated antioxidant marker genes (NRF2 and HO-1) and up-regulated mRNA expression of CD44 with no significant difference in OPN when compared with control. TGAMLE and its derived compounds significantly activated the NRF2/HO-1 pathway by up-regulating its expression and modify crystal binding molecules (CD44/OPN). Overall, the additive effects of the compounds present in the extract revealed a better efficacy in attenuating NRF2/HO-1 pathway as well as the expression of crystal binding molecules. Conclusion: The present study concludes the nephro-protective effect and underlying mechanism of TGAMLE against ethane-1,2-diol exposed rats and suggests that TGAMLE or compounds in TGAMLE could be an alternative agent against kidney stones.