Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is -hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for -hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Citrate intersects multiple biochemical pathways, yet its role in cancer has received limited attention. Similarly, the Na+-coupled citrate transporter (SLC13A5) has been investigated extensively in connection with epileptic encephalopathy, but its relevance to cancer remains understudied. This review focuses on novel insights into citrate biology and SLC13A5 that suggest a tumor-promoting role for SLC13A5/citrate. Cytosolic citrate is the building block for fatty acid and cholesterol synthesis necessary for membrane biogenesis and serves as a signaling molecule in regulating mitophagy and proteostasis in endoplasmic reticulum. Cytosolic citrate pools derived from SLC13A5-mediated uptake across the plasma membrane and SLC25A1-mediated export from mitochondria have distinct functions. Citrate inhibits asparaginyl hydroxylase and thus potentiates the transcription via hypoxia-inducible factors, consequently enhancing lactatogenic aerobic glycolysis and glutaminolysis in cancer cells. Citrate chelates iron and zinc; hence cancer cells may be protected from ferroptosis and subjected to metabolic alterations by citrate. Human SLC13A5 is coupled to Na+ and H+, a feature that accelerates the delivery of extracellular citrate into cancer cells in the acidic tumor microenvironment (TME). SLC13A5 is also expressed in intracellular vesicles where it sequesters cytoplasmic citrate, thereby relieving citrate-mediated inhibition of glycolysis. Because bone matrix is rich in citrate, osteolytic bone metastasis may increase citrate levels in TME, providing a citrate-rich niche that facilitates cancer-cell growth, metabolic reprogramming, and resistance to ferroptosis. Collectively, this review highlights novel biological aspects of citrate and SLC13A5 as they relate to tumor growth and bone metastasis and identifies SLC13A5 as a potential therapeutic target in cancer.

Citrate intersects multiple biochemical pathways, yet its role in cancer has received limited attention. Similarly, the Na⁺-coupled citrate transporter (SLC13A5) has been investigated extensively in connection with epileptic encephalopathy, but its relevance to cancer remains understudied. This review focuses on novel insights into citrate biology and SLC13A5 that suggest a tumor-promoting role for SLC13A5/citrate. Cytosolic citrate is the building block for fatty acid and cholesterol synthesis necessary for membrane biogenesis and serves as a signaling molecule in regulating mitophagy and proteostasis in the endoplasmic reticulum. Cytosolic citrate pools derived from SLC13A5-mediated uptake across the plasma membrane and SLC25A1-mediated export from mitochondria have distinct functions. Citrate inhibits asparaginyl hydroxylase and thus potentiates transcription via hypoxia-inducible factors, consequently enhancing lactatogenic aerobic glycolysis and glutaminolysis in cancer cells. Citrate chelates iron and zinc; hence, cancer cells may be protected from ferroptosis and subjected to metabolic alterations by citrate. Human SLC13A5 is coupled to Na⁺ and H⁺, a feature that accelerates the delivery of extracellular citrate into cancer cells in the acidic tumor microenvironment (TME). SLC13A5 is also expressed in intracellular vesicles where it sequesters cytoplasmic citrate, thereby relieving citrate-mediated inhibition of glycolysis. Because the bone matrix is rich in citrate, osteolytic bone metastasis may increase citrate levels in the TME, providing a citrate-rich niche that facilitates cancer cell growth, metabolic reprogramming, and resistance to ferroptosis. Collectively, this review highlights novel biological aspects of citrate and SLC13A5 as they relate to tumor growth and bone metastasis and identifies SLC13A5 as a potential therapeutic target in cancer.