In addition to lowering blood glucose and selectively starving tumor cells by restricting carbohydrates, the high fat content of the ketogenic diet can create physiological ketonemia, and the metabolites can regulate key pathways in tumor development, thus acting as an anti-tumor agent, Figure 2. 4.1 Ketogenic diet and IGF1/Akt/mTOR Bielohuby M et al. To investigate the effects of major nutrients on the growth hormone (GH) signaling pathway, 12-week-old rats were randomly divided into three groups and given a normal diet, a protein-matched diet and a ketogenic diet (fat/protein/carbohydrate ratios of 16, 7/19/64, 3, 78, 7/19, 1/2, 2 and 92, 8/5, 5/1, 7, respectively). After 4 weeks, IGF1, IGFBP1, and IGFBP3 were significantly reduced with the reduction of carbohydrates in the diet. IGF1, once bound to its receptor, can activate Akt or MAPK, which are involved in tumorigenesis, angiogenesis and metastasis. The suppression of IGF1 is also closely associated with the effect of KD in promoting chemotherapy or radiotherapy, especially in tumors without PI3K activating mutations. 4.2 Ketogenic diet and ROS Tumor cells are always in a state of mild oxidative stress due to impaired mitochondrial function, and Milder J et al. found that GSH levels were decreased in the hippocampus and liver of KD-fed rats, while the lipid peroxidation metabolite 4HNE was significantly upregulated, by a mechanism related to the activation of the transcription factor NrF2 pathway by ketone bodies. It is suggested that elevated ketone bodies at KD may improve the efficacy of radiotherapy for lung cancer and glioblastoma through the ROS pathway or by affecting the response of tumor cells to oxidative stress. 4.3 Ketogenic diet and AMPK Tumor cells rely on glucose as their main energy source. A low-carbohydrate diet leads to an increase in AMP/ATP ratio and activation of AMPK, which can negatively regulate the Akt/mTOR pathway on the one hand, and inhibit key enzymes in the metabolic pathway such as PFK2 and ACC in synergy with PPARĪ± on the other hand, inhibiting glycolysis and fatty acid synthesis and specifically 4.4 Ketogenic diet and metabolism 4.4 Ketogenic diet and metabolic pathways Normal cells can maintain their homeostasis by systematically regulating metabolic pathways (decreasing synthetic signals and increasing catabolic signals) when they are undernourished. Lee C et al. found that the apoptosis rate of tumor cells was significantly higher than that of normal cells under starvation conditions, thus improving the efficacy of chemotherapy.