With the release of an online video about the successful treatment of advanced cancer with ketogenic diet, dozens of tumor patients and their family members are asking about ketogenic diet for tumor and cancer related issues every day. What is the history of ketogenic diet? The ketogenic diet originated in the biblical era and has been used mainly in patients with refractory epilepsy, with large-scale clinical evidence proving its conclusive efficacy, while its role in metabolic diseases such as pyruvate dehydrogenase deficiency, neurodegenerative pathologies such as Parkinson’s disease and Alzheimer’s disease, psychiatric diseases such as depression and bipolar disorder, and malignant tumors such as glioblastoma and prostate cancer has also been effectively confirmed. I. What is the ketogenic diet? A ketogenic diet is a diet with a high percentage of fat, appropriate protein and low carbohydrates. Because our normal diet does not produce ketone bodies, the ketogenic diet is a dietary treatment designed to produce ketone bodies in the body, hence the name ketogenic diet. How are ketone bodies produced? Under daily dietary conditions, the body converts carbohydrates into glucose, which enters the oxidative phosphorylation pathway to produce ATP to sustain life activities. Under low sugar intake conditions (e.g., starvation, high-fat diet), the body supplies energy through fat hydrolysis: fatty acids are produced in the liver through β-oxidation to produce ketone bodies, including acetoacetate, β-hydroxybutyrate and acetone, which are then transported to other tissues and organs to replace glucose as a source of ATP. source of ATP. The ketogenic diet (KD) replaces carbohydrates with fats as the main energy source and induces physiological ketonemia in the body. The metabolic characteristics of tumor cells are thought to be closely related to the malignant genome, mitochondrial damage and hypoxic microenvironment. The malignant transformation process of normal cells is accompanied by activation and/or inactivation of a series of oncogenes, and these genomic alterations can cause a shift in cellular metabolic patterns and energy sources through the corresponding pathways. When the oncogene P53 is inactivated by mutation or epistasis, aerobic glycolysis is increased and oxidative phosphorylation is inhibited. Extensive deleterious mutations of PTEN in tumor tissues can cause hyperactivation of the Akt/mTOR pathway, which plays an important regulatory role in tumor metabolism. The activation of oncogenes PIK3CA and Ras can cause changes in the metabolic pathways of tumor cells, eventually leading to a shift from the oxidative phosphorylation pathway to the glycolytic pathway for ATP production. mitochondria play an important role in cellular respiration, energy metabolism and apoptotic signaling, and alterations in their function or structure lead to a significant reduction in apoptosis and impairment of the phosphorylation pathway in tumor cells. In addition, the central oxygen concentration in cancer nests was significantly reduced, suggesting that tumor cells were in a relatively hypoxic microenvironment. Unlike normal cells that can utilize ketone bodies when glucose is deficient, malignant transformed cells cannot dynamically adapt to environmental nutrient changes due to genomic alterations, mitochondrial structural or functional damage and insufficient relative oxygen supply make tumor cells singularly dependent on glycolysis for ATP, and thus tumor cells are more sensitive to glucose deficiency than normal cells Figure 1. Although neurons and glial cells preferentially utilize glucose as energy source, once glucose is deficient, they can turn to ketone bodies as the main energy donor. However, it has been found that succinyl-CoA:3-ketoacid CoA transferase (SCOT), a key enzyme in ketone body energy supply metabolism, is down-regulated in a variety of brain tumors, indicating impaired ketone body utilization in tumor cells. Both in vitro cultured tumor cells and in vivo animal models have confirmed that brain malignancies, especially glioblastoma, are highly dependent on glucose for energy supply. Clinical evidence of ketogenic diet for cancer treatment 1. Ketogenic diet can specifically target the metabolic changes of tumor cells, and its anti-tumor effects have been confirmed by different scholars in various tumor models such as brain malignancy, prostate cancer, gastric cancer, lung cancer and head and neck tumors. 2. Ketogenic diet can improve the prognosis of patients with grade III-IV glioblastoma multiforme, and the mechanism is related to its significant reduction of blood glucose level. The prognosis of tumor patients was significantly improved by the increase of β-hydroxybutyric acid level in blood when treated with ketogenic diet, and the mechanism was related to the reduction of reactive oxigen species (ROS). In addition, gene expression profiling suggested a trend of reversal of tumor gene expression to non-tumor tissues during ketogenic diet treatment. The tumor can be in complete remission with ketogenic diet treatment, and there is no sign of tumor recurrence after one year of treatment, suggesting that the anti-tumor effect of ketogenic diet is sustainable. In addition to protecting normal tissues from radiotherapy and sensitizing tumor tissues, ketogenic diet can also maintain the skeletal muscle quality of HNSCC patients, thus improving their prognosis.