Folate transport system (Reduced folate carrier and Folate receptors) (RFC/FR)

The folate transport system, primarily comprising the Reduced Folate Carrier (SLC19A1) and Folate Receptors (notably FOLR1), is essential for the cellular uptake of folates required for DNA synthesis, repair, and methylation [1][2]. SLC19A1 is a ubiquitously expressed solute carrier that acts as an organic phosphate/folate antiporter and is the major entry route for reduced folates and antifolate chemotherapeutics like methotrexate [1][3]. Folate receptors, such as Folate Receptor Alpha (FOLR1), are GPI-anchored proteins that mediate folate uptake via receptor-mediated endocytosis and are frequently overexpressed in epithelial tumors (e.g., ovarian, lung, and breast cancers) while maintaining low expression in normal tissues [4][5]. This differential expression makes FOLR1 a high-value target for antibody-drug conjugates, such as mirvetuximab sortansine, and imaging agents [6]. Conversely, SLC19A1 is a critical determinant of the efficacy and resistance of classical antifolates, as its downregulation or mutation can lead to reduced drug uptake and treatment failure [1][7]. Together, these transporters maintain folate homeostasis, and their dysfunction is linked to developmental disorders, anemia, and oncogenic progression [2][4].

Other names

Reduced folate carrierRFCSLC19A1Folate receptor alphaFOLR1Folate binding proteinFBPMembrane folate binding proteinSolute carrier family 19 member 1

Drugs targeting these proteins act as substrates for cellular uptake to inhibit intracellular folate-dependent enzymes or as ligands for receptor-mediated endocytosis to deliver cytotoxic payloads.