Slc19a1, also known as the reduced folate carrier, is a folate-organic phosphate antiporter. It plays a crucial role in multiple physiological and pathological processes. It is the major transporter for folate nutrients, antifolate therapeutics, and immunoreactive cyclic dinucleotides (CDNs) [1,2,3,8]. The accumulation of cytosolic DNA activates the cGAS-STING pathway, and CDNs produced must cross the cell membrane to activate STING, a process dependent on Slc19a1 [1,2,3].

Genome-wide CRISPR-interference screens and functional studies have shown that depleting Slc19a1 in human cells inhibits CDN uptake and functional responses, while overexpressing it increases both uptake and responses [1,3]. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates, sulfasalazine, and methotrexate [1]. Structures of human Slc19a1 have revealed unique mechanisms for recognizing CDN-and folate-type substrates [2]. Additionally, in osteosarcoma, Slc19a1 is highly expressed and may serve as a biomarker for diagnosis and prognosis [4]. Its 80G>A genetic variation is associated with increased susceptibility to nonsyndromic cleft lip with or without cleft palate [5], and the rs1051296 G>T polymorphism is a risk factor for preeclampsia in the Pakistani population [6]. In multiple myeloma, it is a hypoxia-immune-related gene and highly expressed SLC19A1 might be a biomarker correlated with inferior prognosis [7].

In conclusion, Slc19a1 is essential for the transport of key molecules like folates and CDNs, playing a significant role in immune responses, cancer, and other disease conditions. Model-based research, such as genome-wide CRISPR-interference screens in human cells, has been instrumental in uncovering its functions in these biological processes and disease areas.