Slc27a5, also known as FATP5, is a key enzyme involved in fatty acid transport and bile acid metabolism in the liver [2,3,4,5,6,7]. It participates in important biological pathways related to lipid and bile acid homeostasis, which are crucial for normal liver function and overall metabolism. Genetic models, such as knockout mouse models, have been valuable in studying its functions.

In mice, Slc27a5 knockout (Slc27a5 -/-) leads to spontaneous liver fibrosis after 24 months and aggravates liver fibrosis induced by carbon tetrachloride and thioacetamide. This is due to the accumulation of unconjugated bile acid, particularly cholic acid, which activates hepatic stellate cells [1]. In hepatocellular carcinoma (HCC), Slc27a5 deficiency promotes sorafenib resistance by suppressing ferroptosis through enhancing glutathione reductase expression in an NRF2 -dependent manner [2]. Additionally, knockout of Slc27a5 in HCC cells increases polyunsaturated lipids, leading to increased lipid peroxidation and activation of the KEAP1/NRF2 pathway [3]. Loss of Slc27a5 also results in elevated levels of the PIP4K2A-S isoform, promoting HCC metastasis [4].

In conclusion, Slc27a5 plays essential roles in maintaining normal liver function, especially in lipid and bile acid metabolism. Studies using Slc27a5 knockout mouse models have revealed its significance in liver fibrosis and HCC development, suggesting that it could be a potential target for treating these diseases.

References:

1. Wu, Kang, Liu, Yi, Xia, Jie, Chen, Chang, Tang, Ni. 2023. Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2304408. doi:10.1002/advs.202304408. https://pubmed.ncbi.nlm.nih.gov/37957540/

2. Xu, Feng-Li, Wu, Xiao-Hong, Chen, Chang, Shan, Xue-Feng, Tang, Ni. 2023. SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase. In Cell death & disease, 14, 22. doi:10.1038/s41419-023-05558-w. https://pubmed.ncbi.nlm.nih.gov/36635256/

3. Gao, Qingzhu, Zhang, Guiji, Zheng, Yaqiu, Wang, Kai, Tang, Ni. 2019. SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC. In Cell death and differentiation, 27, 1086-1104. doi:10.1038/s41418-019-0399-1. https://pubmed.ncbi.nlm.nih.gov/31367013/

4. Nie, Dan, Tang, Xin, Deng, Haijun, Huang, Ailong, Tang, Ni. 2023. Metabolic Enzyme SLC27A5 Regulates PIP4K2A pre-mRNA Splicing as a Noncanonical Mechanism to Suppress Hepatocellular Carcinoma Metastasis. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2305374. doi:10.1002/advs.202305374. https://pubmed.ncbi.nlm.nih.gov/38059827/

5. Wang, Jiyan, Qiao, Yaya, Sun, Huanran, Zhang, Shuai, Shan, Changliang. 2022. Decreased SLC27A5 Suppresses Lipid Synthesis and Tyrosine Metabolism to Activate the Cell Cycle in Hepatocellular Carcinoma. In Biomedicines, 10, . doi:10.3390/biomedicines10020234. https://pubmed.ncbi.nlm.nih.gov/35203444/

6. Zhang, Fan, Xue, Mengjuan, Jiang, Xin, Yang, Fan, Bao, Zhijun. 2021. Identifying SLC27A5 as a potential prognostic marker of hepatocellular carcinoma by weighted gene co-expression network analysis and in vitro assays. In Cancer cell international, 21, 174. doi:10.1186/s12935-021-01871-6. https://pubmed.ncbi.nlm.nih.gov/33731144/

7. Tao, Junji, Liu, Yuanyuan, Tang, Xin, Wang, Kai, Tang, Ni. 2025. Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A. In Biochimica et biophysica acta. Molecular cell research, 1872, 119916. doi:10.1016/j.bbamcr.2025.119916. https://pubmed.ncbi.nlm.nih.gov/39938688/