Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer.
- 1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
- 2Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA.
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 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.
Related
- Solute carrier transporters as metabolic gatekeepers in tumor-microenvironment crosstalk
- Platelet Membrane Transporters in Health and Disease: Basic Biology and Clinical Relevance
- Stemness-Associated Biomarkers in Breast Cancer Liver Metastasis: Hepatic Adaptation, Prognostic Relevance, and Monitoring
- Immune checkpoint blockade activates macrophages and remodels the lymph node microenvironment in melanoma metastasis
- Editorial: The insights of multi-omics into the microenvironment after tumor metastasis: a paradigm shift in molecular targeting modeling and immunotherapy for advanced cancer patients, volume II
BibTeX
@article{ganapathy2026novel,
title = {{Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer.}},
author = {Vadivel Ganapathy and Sathish Sivaprakasam and Yangzom D Bhutia and Puttur D Prasad and Muthusamy Thangaraju},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15191811},
url = {https://europepmc.org/article/MED/42882509},
note = {CC BY},
}
RIS
TY - JOUR
TI - Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer.
AU - Vadivel Ganapathy
AU - Sathish Sivaprakasam
AU - Yangzom D Bhutia
AU - Puttur D Prasad
AU - Muthusamy Thangaraju
PY - 2026
DA - 2026/10/04
JO - Cells
DO - 10.3390/cells15191811
UR - https://europepmc.org/article/MED/42882509
AB - 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.
SN - 2073-4409
ER -