Slc45a4, a member of the solute carrier family 45, is a H⁺ -dependent sugar cotransporter. It has been implicated in multiple biological functions, including sugar transport, with the ability to transport sucrose, glucose, and fructose [6,7]. It also seems to be involved in pathways related to γ -aminobutyric acid (GABA) de novo synthesis [3]. Additionally, its expression has been associated with pigmentation regulation [4], and it may play a role in spermatozoa nutrition during maturation in the epididymis [6].

In cancer research, loss-of-function experiments have provided key insights. In ovarian cancer, silencing of Slc45a4 significantly inhibited the proliferation, invasion, and metastasis of ovarian cancer cells by suppressing glucose uptake and glycolysis, and also reduced the expression of the HIF-α glycolysis signaling pathway [1]. In TP53 mutant pancreatic ductal adenocarcinoma, knockdown of Slc45a4 inhibited cell proliferation, reduced glucose uptake and ATP production, leading to autophagy activation via the AMPK/ULK1 pathway, and also inhibited xenograft growth in nude mice [2]. In gastric cancer, the PVT1-214/miR-671-5p/Slc45A4 signaling axis was found to regulate cell proliferation, where PVT1-214 positively regulates Slc45A4 expression through competitive binding to miR-671-5p [5].

In summary, Slc45a4 is involved in sugar transport, GABA synthesis, and pigmentation regulation. In the context of cancer, gene knockdown studies in mouse models have revealed its significance in promoting cancer cell proliferation, invasion, and metastasis through glycolytic metabolic reprogramming and prevention of autophagy. These findings suggest its potential as a therapeutic target in ovarian, pancreatic, and gastric cancers [1,2,5].

References:

1. Xu, Yuance, Han, Xiahui, You, Shijing, He, Junqi, Yao, Qin. 2024. SLC45A4 is involved in malignant progression of ovarian cancer through glycolytic metabolic reprogramming. In Scientific reports, 14, 23031. doi:10.1038/s41598-024-74249-z. https://pubmed.ncbi.nlm.nih.gov/39363015/

2. Chen, Wenying, Huang, Fengting, Huang, Jing, Zhu, Zhe, Zhang, Shineng. 2021. SLC45A4 promotes glycolysis and prevents AMPK/ULK1-induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma. In The journal of gene medicine, 23, e3364. doi:10.1002/jgm.3364. https://pubmed.ncbi.nlm.nih.gov/34010493/

3. Colson, Cecilia, Wang, Yujue, Atherton, James, Su, Xiaoyang. 2024. SLC45A4 encodes a mitochondrial putrescine transporter that promotes GABA de novo synthesis. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.07.23.604788. https://pubmed.ncbi.nlm.nih.gov/39091866/

4. Brito, Sofia, Heo, Hyojin, Cha, Byungsun, Weon, Byung Mook, Bin, Bum-Ho. 2023. The Slc45a4 Gene Regulates Pigmentation in a Manner Distinct from that of the OCA4 Gene Slc45a2. In The Journal of investigative dermatology, 144, 720-722.e5. doi:10.1016/j.jid.2023.08.027. https://pubmed.ncbi.nlm.nih.gov/37775036/

5. Yan, Wei, Wang, Huizhen, Zhao, Yong, Zhang, Weitong, Li, Yongxiang. 2025. The PVT1-214/miR-671-5p/SLC45A4 signaling axis regulates cell proliferation in human gastric cancer. In World journal of surgical oncology, 23, 158. doi:10.1186/s12957-025-03805-2. https://pubmed.ncbi.nlm.nih.gov/40275296/

6. Vitavska, Olga, Wieczorek, Helmut. 2017. Putative role of an SLC45 H+/sugar cotransporter in mammalian spermatozoa. In Pflugers Archiv : European journal of physiology, 469, 1433-1442. doi:10.1007/s00424-017-2024-9. https://pubmed.ncbi.nlm.nih.gov/28689241/

7. Bartölke, Rabea, Heinisch, Jürgen J, Wieczorek, Helmut, Vitavska, Olga. . Proton-associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. In The Biochemical journal, 464, 193-201. doi:10.1042/BJ20140572. https://pubmed.ncbi.nlm.nih.gov/25164149/