Inhibition of ALDOA and ENO1‐mediated Glycolysis of Oridonin as a Novel Anti‐tumor Strategy of Non‐small Cell Lung Cancer

Abstract Non‐small‐cell lung cancer (NSCLC) is the most common type of lung cancer. Oridonin (ORI), the main pharmacodynamic component of the Chinese herb Herba Rabdosiae with anticancer activity is reported to inhibit various types of cancer including NSCLC. However, its direct target proteins acting on NSCLC still require further investigation. Here, the direct protein profile is analyzed and the key targets of ORI are identified by combining activity‐based protein profiling (ABPP) and the cellular thermal shift assay (CETSA). As a result, ORI can significantly promote Lewis Lung Carcinoma (LLC) cell apoptosis, decrease mitochondrial membrane potential, and increase reactive oxygen species accumulation. In addition, both ABPP and CETSA indicate that ORI directly binds to key proteins of the glycolysis pathway, including Aldolase A (ALDOA), Enolase 1 (ENO1), pyruvate kinase M2, and lactate dehydrogenase. Based on the LLC mouse model, ORI markedly inhibits the growth of lung tumors, increases the serum levels of antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase, and reduces the production of malondialdehyde. To sum up, ORI can be regarded as a novel antitumor strategy of NSCLC by inhibiting ALDOA‐ and ENO1‐mediated glycolysis.