Regarding the major seven enzymes catalyzing the irreversible steps in gluconeogenesis, we identified and quantified three enzymes in our proteomic analysis, including PEPCK-M, MDH1 and mitochondrial malate dehydrogenase. MDH1 was significantly up-regulated 1.93-fold with Talazoparib treatment of citreoviridin. Although the expression levels of MDH2 and PEPCK-M showed no significant up-regulation, these two enzymes had higher expression levels in citreoviridin-treated tumors than control tumors. Is it possible that gluconeogenesis occurs in cancer cells when treated with citreoviridin? The whole proteomic profiling of control and citreoviridin-treated tumors may provide some hints. The expression level of several other proteins related to glucose metabolism was changed with citreoviridin treatment. These proteins are involved in synthesis of glycogen from glucose, conversion of glucose to inositol or sorbitol and glucose transport. The expression levels of three enzymes, which convert glucose to other compounds, were higher in the citreoviridin-treated tumors. The first one is UTP-glucose-1-phosphate uridylyltransferase, which catalyzes the reaction of converting glucose 1-phosphate to UDP-glucose, the immediate donor of glucose for glycogen synthesis. The second one is inositol- 3-phosphate synthase 1, which catalyzes the conversion of glucose 6-phosphate to 1-myo-inositol 3-phosphate. Third, aldose reductase reduces glucose to sorbitol, which accumulated in the cells in response to hyperosmotic stress that causes shrinkage of the cells. Surplus glucose enters the polyol pathway by converting to sorbitol catalyzed by aldose reductase. From the above observations, glucose might be overproduced in cancer cells with treatment of citreoviridin. We also noticed that the expression level of glucose transporter GLUT-3 was lower with the treatment of citreoviridin, which indicated that excess glucose mainly came from gluconeogenesis. Citreoviridin was shown to suppress lung adenocarcinoma growth by targeting ectopic ATP-synthase. The observation of activated gluconeogenesis by citreoviridin in the proteomic profiling raised the question of whether there is a relationship between gluconeogenesis and inhibition of lung cancer cell proliferation. There are only limited literatures describing the effects of gluconeogenesis on cancer and most of them were reported in the 1970s. The role of gluconeogenesis in cancer cells can vary depending on the gluconeogenic precursors, including lactate, pyruvate, amino acids and other metabolites. It was suggested that gluconeogenesis from alanine is increased in cancer patients with SCH772984 cachexia, a syndrome with significant loss of appetite resulting in weakness and loss of weight.