As one of the most common cancer chemotherapy drugs, cisplatin is widely used in cancer management. However, cisplatin-induced nephrotoxicity occurs in patients who receive this drug. This study is aimed at developing therapeutic agents that effectively alleviate the nephrotoxic effects during cisplatin treatment. We identified a compound named pyrocatechol (PCL) from a natural product library that significantly alleviated cisplatin-induced cytotoxicity in vitro. Pyrocatechol treatment substantially ameliorated cisplatin (20 mg · kg-1) treatment-induced neuropathological indexes, including inflammatory cell infiltration and apoptosis, in vivo. Mechanistically, pyrocatechol significantly prevented oxidative stress-induced apoptosis by activating glutathione peroxidase 4 (GPX4) to reduce reactive oxygen species (ROS) accumulation in cisplatin-treated cells. In addition, pyrocatechol significantly inhibited ROS-induced JNK/P38 activation. Thus, we found that pyrocatechol prevents ROS-mediated JNK/P38 MAPK activation, apoptosis, and cytotoxicity through GPX4. Our study demonstrated that pyrocatechol is a novel therapeutic agent against cisplatin-induced kidney injury.
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