Sfxn1, or sideroflexin 1, is a multipass inner mitochondrial membrane protein. It functions as a mitochondrial serine transporter in one-carbon metabolism, a pathway crucial for synthesizing critical metabolites like nucleotides [1]. One-carbon metabolism has cytosolic and mitochondrial branches, and Sfxn1-mediated serine entry into mitochondria is a key step where serine is converted into glycine and formate [1].

In genetic studies, SFXN1-null human cells are defective in glycine and purine synthesis, similar to cells lacking other mitochondrial components of one-carbon metabolism [1]. In zebrafish, knockdown and knockout of sfxn1 result in hypochromic anemia due to hemoglobin biosynthetic deficiency, caused by heme biosynthetic disorder associated with the mitochondrial branch of one-carbon metabolism in erythrocytes [3].

In lung adenocarcinoma (LUAD), SFXN1 is upregulated and associated with poor prognosis. RNA-seq and scRNA-seq analyses show increased SFXN1 expression in tumor cells accompanied by decreased infiltration of NK and cytotoxic T cells. SFXN1 knockdown reduces cell proliferation and migration in LUAD cells [2].

In non-viral hepatocellular carcinoma, loss of SFXN1 expression suppresses lipid accumulation and ROS generation, predicting clinical outcome [4].

In triple-negative breast cancer, SFXN1 is overexpressed and promotes tumor growth and metastasis by inhibiting TOLLIP-mediated autophagic degradation of CIP2A [5].

In conclusion, Sfxn1 is essential for one-carbon metabolism, especially for serine transport into mitochondria. Gene knockout studies in different model organisms and cell lines have revealed its role in various biological processes and disease conditions such as anemia, cancer (LUAD, non-viral HCC, triple-negative breast cancer). These findings enhance our understanding of the biological functions of Sfxn1 and its potential as a therapeutic target in related diseases.