Slc7a11, also commonly known as xCT, is a key component of the cystine/glutamate antiporter system Xc-. It imports cystine for glutathione biosynthesis and antioxidant defense, playing a crucial role in cellular redox homeostasis and regulating processes like ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation [1,3].

In HCC, hepatocyte-specific ATF4-deficient MUP-uPA mice showed increased susceptibility to ferroptosis and accelerated HCC development due to decreased Slc7a11 expression. Re-expressing Slc7a11 reversed ferroptosis susceptibility and hepatocarcinogenesis, indicating its protective role in normal hepatocytes against stress-related ferroptosis [2]. In breast cancer, metformin induced ferroptosis by inhibiting the UFMylation of Slc7a11, reducing its protein stability and thus suppressing tumor growth [4].

In summary, Slc7a11 is essential for maintaining cellular redox balance and protecting cells from ferroptosis. Studies using gene-knockout mouse models in HCC and breast cancer have revealed its significant roles in these disease contexts, highlighting its potential as a therapeutic target for cancer treatment.

References:

1. Koppula, Pranavi, Zhuang, Li, Gan, Boyi. 2020. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. In Protein & cell, 12, 599-620. doi:10.1007/s13238-020-00789-5. https://pubmed.ncbi.nlm.nih.gov/33000412/

2. He, Feng, Zhang, Peng, Liu, Junlai, Yaden, Benjamin C, Karin, Michael. 2023. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. In Journal of hepatology, 79, 362-377. doi:10.1016/j.jhep.2023.03.016. https://pubmed.ncbi.nlm.nih.gov/36996941/

3. Lin, Wenyu, Wang, Chaoqun, Liu, Guangping, Zhou, Qiyin, Jin, Hongchuan. 2020. SLC7A11/xCT in cancer: biological functions and therapeutic implications. In American journal of cancer research, 10, 3106-3126. doi:. https://pubmed.ncbi.nlm.nih.gov/33163260/

4. Yang, Jingjing, Zhou, Yulu, Xie, Shuduo, Wang, Linbo, Zhou, Jichun. 2021. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. In Journal of experimental & clinical cancer research : CR, 40, 206. doi:10.1186/s13046-021-02012-7. https://pubmed.ncbi.nlm.nih.gov/34162423/