Slc28a3, also known as human Concentrative Nucleoside Transporter 3 (hCNT3), is a membrane transporter that belongs to the solute carrier family 28. It mediates the salvage of nucleosides and the transport of therapeutic nucleoside analogues across plasma membranes by coupling ligand transport to the sodium gradient [6]. It forms a cyclic homotrimer, and oligomerization seems crucial to its stability and function [6].

Multiple studies have explored the role of Slc28a3 in various disease-related contexts. In chemotherapy-induced cardiotoxicity, genomic variants in Slc28a3, such as rs7853758 and rs885004, are associated with a lower incidence of anthracycline-induced cardiotoxicity. Patient-derived cardiomyocytes and genome-editing techniques like CRISPR/Cas9 have shown that Slc28a3 expression influences the severity of doxorubicin-induced cardiotoxicity (DIC), and a novel cardioprotective single-nucleotide polymorphism, rs11140490, in the Slc28a3 locus exerts its effect via regulating an antisense long non-coding RNA (SLC28A3-AS1) [1]. Knockout of Slc28a3 in isogenic human-induced pluripotent stem cell-derived cardiomyocytes demonstrated a protective effect against DIC [5]. In Chinese liver transplantation patients, the rs7853758 variant in recipients' Slc28a3 could predict tacrolimus pharmacokinetics and was a new risk factor for new-onset hypertension after liver transplantation [2]. In chronic lymphocytic leukemia patients with intact TP53, higher pretreatment levels of Slc28a3 mRNA were detected in patients who failed to respond to fludarabine plus cyclophosphamide chemotherapy [3]. In patients with solid tumours, the presence of the homozygous major allele for Slc28a3 (CC genotype) was associated with an almost two-fold increase in the formation clearance of dFdCTP, a metabolite of gemcitabine [4].

In summary, Slc28a3 plays important roles in multiple disease-related processes, especially in chemotherapy-induced cardiotoxicity, drug metabolism, and treatment response. Studies using genetic manipulation models, such as gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes, have been crucial in revealing its functions in these disease areas [1,2,3,4,5].

References:

1. Magdy, Tarek, Jouni, Mariam, Kuo, Hui-Hsuan, Bernstein, Daniel, Burridge, Paul W. 2021. Identification of Drug Transporter Genomic Variants and Inhibitors That Protect Against Doxorubicin-Induced Cardiotoxicity. In Circulation, 145, 279-294. doi:10.1161/CIRCULATIONAHA.121.055801. https://pubmed.ncbi.nlm.nih.gov/34874743/

2. Liu, Yuan, Zhang, Tao, Li, Changcan, Peng, Zhihai, Fan, Junwei. 2017. SLC28A3 rs7853758 as a new biomarker of tacrolimus elimination and new-onset hypertension in Chinese liver transplantation patients. In Biomarkers in medicine, 11, 607-618. doi:10.2217/bmm-2017-0128. https://pubmed.ncbi.nlm.nih.gov/28621555/

3. Vukovic, Vojin, Karan-Djurasevic, Teodora, Antic, Darko, Pavlovic, Sonja, Mihaljevic, Biljana. 2019. Association of SLC28A3 Gene Expression and CYP2B6*6 Allele with the Response to Fludarabine Plus Cyclophosphamide in Chronic Lymphocytic Leukemia Patients. In Pathology oncology research : POR, 26, 743-752. doi:10.1007/s12253-019-00613-4. https://pubmed.ncbi.nlm.nih.gov/30778771/

4. Khatri, A, Williams, B W, Fisher, J, Lamba, J K, Kirstein, M N. 2013. SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours. In British journal of cancer, 110, 304-12. doi:10.1038/bjc.2013.738. https://pubmed.ncbi.nlm.nih.gov/24300978/

5. Fonoudi, Hananeh, Jouni, Mariam, Cejas, Romina B, Sapkota, Yadav, Burridge, Paul W. 2024. Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes. In JACC. CardioOncology, 6, 38-50. doi:10.1016/j.jaccao.2023.11.008. https://pubmed.ncbi.nlm.nih.gov/38510289/

6. Stecula, Adrian, Schlessinger, Avner, Giacomini, Kathleen M, Sali, Andrej. 2017. Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer. In Biochemistry, 56, 3475-3483. doi:10.1021/acs.biochem.7b00339. https://pubmed.ncbi.nlm.nih.gov/28661652/