Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer
Year: 2026
Type: review
Abstract: 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.
Source: Cells
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7204816019