Evaluating the implications of K-Ras, KEAP1/NRF2-mediated signaling pathways and metabolic alterations in urethane-induced lung cancer.

Lung cancer, being an aggressive malignancy, is a leading cause of cancer-related mortality worldwide. Urethane, a genotoxic chemical, is a highly potent carcinogen in the development of lung cancer. Understanding the molecular mechanisms related to oxidative stress and metabolic anomalies involved in lung malignancy caused by urethane is of utmost importance. Male C57BL/6 mice were used to generate a urethane-induced lung cancer model. Urethane-exposed animals demonstrated cancerous lesions, loss of normal pulmonary architecture, and condensed alveolar structure. Urethane exposure upregulated K-Ras and downregulated p53 in the induced group. The induced rats also showed a decrease in Kelch-like ECH-associated protein 1 (KEAP1), Cullin3 (CUL3) and upregulated nuclear factor erythroid 2–related factor 2 (NRF2) and Heme oxygenase-1 (HO-1). Metabolomics studies identified that urethane exposure impacted the citric acid cycle, nucleic acid biosynthesis, amino acid, and sugar and lipid metabolism. Crucial metabolites, such as homocysteine, methylmalonic acid and 5-hydroxytryptamine (5-HT) were found to be upregulated, while tricarboxylic acid (TCA) cycle and fatty acid (FA) cycle metabolites were found to be downregulated in the urethane-induced group. Moreover, a rise in homocysteine was identified in univariate, multivariate, as well as biomarker analysis. Overall, the outcomes of the present study acknowledge the implications of key signaling and metabolic pathway modulations by urethane treatment, whose dysregulation might be associated with lung carcinogenesis.