Methyl jasmonate mitigates cisplatin-induced nephrotoxicity via modulation of Caspase-3/COX-2/ NF-κB signalling pathway: In silico, In vitro, and In vivo investigations

Cisplatin is a widely used chemotherapeutic agent; however, its clinical utility is limited due to several organ toxicities, including nephrotoxicity, which is primarily mediated through oxidative stress, inflammation, and apoptosis. This study examines the protective effect of methyl jasmonate (MeJA) in mitigating cisplatin-induced nephrotoxicity by modulating the caspase-3/COX-2/NF-κB signaling pathway. Initially, we performed molecular docking to evaluate the binding affinity of MeJA against the caspase-3, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) proteins in the presence of the reference drug amifostine. Further, in vitro cell cytotoxicity on Madin-Darby canine kidney (MDCK) cells via MTT assay, oxidative stress, and proinflammatory markers. We have also performed an in vivo analysis of MeJA on cisplatin-induced nephrotoxicity in experimental rats by employing several biochemical parameters and histopathological investigation on rat kidney tissues. In silico molecular docking analysis revealed strong binding interactions between MeJA, key apoptotic and inflammatory mediators, suggesting its potential to regulate cisplatin-induced toxicity. In vitro studies using MDCK cells demonstrated that MeJA significantly reduced cisplatin-induced cytotoxicity, oxidative stress, and proinflammatory markers. In vivo experiments in rats further confirmed the nephroprotective effects of MeJA, as evidenced by improved renal function markers, and histopathological preservation of renal tubules and glomerulus tissues of rat kidneys. While ELISA testing revealed that MeJA downregulates caspase-3 and COX-2 expression and suppresses NF-κB activation. These findings collectively highlight the therapeutic potential of MeJA in alleviating cisplatin-induced nephrotoxicity through modulation of apoptosis and inflammatory pathways. MeJA may serve as a promising nephroprotective agent, warranting further clinical investigation for its potential application in oncology settings.