Protective role of ursolic acid against cisplatin-induced oxidative stress and ferroptosis in the liver of Swiss albino mice.

Abstract

Cisplatin is a widely used anticancer drug, but its therapeutic use is often limited by systemic toxicities, including hepatotoxicity. Ursolic acid, a natural pentacyclic triterpenoid with antioxidant properties, may help reduce such toxic effects. Recent studies have implicated the role of ferroptosis in cisplatin-induced tissue damage. This study investigates the protective role of ursolic acid against cisplatin-induced liver damage in Swiss albino mice, with a focus on ferroptosis and the expression of TFR1 as well as caspase-3. Mice were divided into five groups (n = 6): Control (DMSO), Cisplatin alone (10 mg/kg), Cis + UA1 (10 mg/kg + 10 mg/kg), Cis + UA2 (10 mg/kg + 40 mg/kg), and UA alone (40 mg/kg). The mice were sacrificed after treatment, and the liver tissues were assessed for biochemical markers (ALT, AST, ALP), oxidative stress (ROS, antioxidant capacity), iron content, and histopathological changes. Immunohistochemical analysis of TFR1 was performed to confirm the involvement of ferroptosis. The expression pattern of caspase-3, which is a crucial executioner of apoptosis, was also evaluated. It was observed that cisplatin intake gradually reduced the body weight and increased the levels of hepatic enzymes. Cisplatin treatment also led to significant increases in ROS levels, iron accumulation, and notable histopathological damage in liver tissue. Mice with ursolic acid treatment demonstrated reduced ROS levels and liver enzymes and also presented with the restoration of antioxidant capacity and improved tissue structure. The expression of the ferroptosis marker TFR1 was also altered in the combination groups along with reduced caspase-3 expression suggesting the attenuation of apoptotic and implication of ferroptosis. This supports the protective role of ursolic acid. These results show that ursolic acid can be an excellent candidate to mitigate the systemic toxic effects of cisplatin and act as an adjuvant in combination with chemotherapies.