Slc7a11, also commonly known as xCT, is the functional component of system Xc-. It acts as a cystine/glutamate antiporter, importing extracellular cystine in exchange for intracellular glutamate at a 1:1 ratio. This function is crucial for glutathione biosynthesis and antioxidant defense, regulating cellular redox homeostasis. It is also involved in pathways related to ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation [1,2,3,4,5,6,7,8,9].

In hepatocellular carcinoma (HCC) research, hepatocyte-specific Atf4-deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) showed increased susceptibility to ferroptosis and accelerated HCC development due to decreased Slc7a11 expression as ATF4 induces Slc7a11 expression. Ectopic expression of Slc7a11 in ATF4-deficient primary hepatocytes and mouse livers reversed ferroptosis susceptibility and hepatocarcinogenesis [2].

In liver fibrosis, sorafenib triggers hepatic stellate cell ferroptosis via the HIF-1α/Slc7a11 pathway, attenuating liver injury and fibrosis as sorafenib reduces Slc7a11 protein levels in hepatic stellate cells [4].

In breast cancer, metformin induces ferroptosis by inhibiting the UFMylation of Slc7a11, reducing its protein stability and suppressing tumor growth [7].

In conclusion, Slc7a11 plays a vital role in maintaining cellular redox balance, especially through its impact on glutathione synthesis. Its function in ferroptosis regulation is significant in diseases such as HCC, liver fibrosis, and breast cancer. Gene knockout or conditional knockout mouse models, like those used in HCC and liver fibrosis studies, have been instrumental in revealing Slc7a11's role in these disease-related biological processes, providing insights into potential therapeutic targets.