Slc25a1, also known as the mitochondrial citrate/isocitrate carrier (CIC), is a key metabolic switch. It belongs to a family of mitochondrial transporters, facilitating the transit of citrate through the mitochondrial membrane. Citrate is central to mitochondrial metabolism and respiration, and in the cytosol, it acts as a metabolic substrate, an allosteric enzymatic regulator, and a source of Acetyl-Coenzyme A for epigenetic modification. Slc25a1 is involved in pathways such as fatty acid oxidation (FAO), fatty acid synthesis, glycolysis, and gluconeogenesis [1,4].

Global knockout of Slc25a1 in mice led to various heart malformations, recapitulating congenital heart defects seen in 22q11.2 deletion syndrome. Trophoblast-specific Slc25a1 deletion also recapitulated heart anomalies, indicating its role in placental development to ensure embryonic heart morphogenesis [2,3]. In pancreatic cancer, oncogenic KRASG12D upregulates Slc25a1 via GLI1, and pharmacologic inhibition of Slc25a1 and upstream GLI1 suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a high-fat diet, revealing a KRASG12D-GLI1-Slc25a1 regulatory axis in pancreatic tumorigenesis [1]. In colorectal cancer, knockdown of Slc25a1 inhibited cell growth by suppressing the G1/S cell cycle progression and inducing apoptosis, while overexpression promoted the malignant phenotype. It reprogrammed energy metabolism to promote cancer progression, increasing de novo lipid synthesis under normal conditions and oxidative phosphorylation during metabolic stress [5].

In conclusion, Slc25a1 is crucial in regulating metabolic reprogramming, embryonic heart morphogenesis, and placental development. Its role in diseases like pancreatic and colorectal cancer, as well as in congenital heart diseases associated with 22q11.2 deletion syndrome, has been revealed through gene knockout mouse models. These studies provide insights into potential therapeutic strategies targeting Slc25a1 for treating related diseases.