Table 1.

Summery of citrate biology in different biological tissues

Location	Specific Target	Function	Mechanism Type	Ref
Microbial	Bacteria	Citric acid inhibits or kills bacteria by reducing intracellular pH	1)	[101–105]
	Bacteria cell wall	Citrate serves as a potent permeabilizer to display antimicrobial effects that synergistic with antibiotics by chelating with Ca2+ and Mg2+	2)	[101, 105, 108,109]
Musculoskeletal system	Bone matrix	Citrate functions as a biomineralization regulator to stabilize bone apatite and control mineralization	2)	[113–119]
	Osteoblast-like cells (MG 63)	Citrate elevates alkaline phosphatase production	Possibly 3)	[72]
	Mesenchymal stem cells (MSCs)	Citrate increases the calcium nodule formation	Possibly 2) and 3)	[135]
Blood and Cardiovascular system	Clotting cascade	Citrate serves as potent anticoagulant agent by chelating with Ca2+	2)	[153, 154]
	Endothelial cells	Citrate reduces endothelial dysfunction, and promotes endothelial sprouting as well as the production of angiogenic growth factors	Possibly 3)	[155, 136]
	Red blood cells	Citrate uptake maintains cell homeostasis by metabolizing into di-carboxylates or transamination intermediates	3)	[156]
	Immune cells (monocytes or lymphocytes)	Citrate serves as biosynthetic substrates for important mediators of inflammation	3)	[97, 98]
Central nerve system	Neuron cells	Citrate regulates neuronal excitability by chelating with cations and/or as energy substrates	2) and/or 3)	[74, 75,174]
Renal system	Renal calcium salts and proteins	Citrate reduces calcium supersaturation and increase the activity of Tamm-Horsfall proteins to prevent renal stone formation	2)	[82]
Cancer	Prostate cancer cells	Citrate enters cells and is consumed to increase their metastasis	3)	[178, 180, 181]
	Liver cancer cells	Citrate uptake serves as energy and biosynthetic substrates to support cell proliferation	3)	[182]
	Gastric, lung, breast and pancreatic cancer	Citrate inhibits cancer cell proliferation by suppressing glycolysis	3)	[183, 184]

¹⁾Note: Reduced pH value;

²⁾Chelation of cations such as Ca²⁺ and Mg²⁺;

³⁾Metabolic regulation