SLC7A11 in liver tissue homeostasis and disease: Cellular mechanisms linking ferroptosis, redox regulation, and hepatic cell survival.

Abstract

Liver diseases involve major disturbances in iron metabolism, redox homeostasis, and lipid peroxidation; therefore, ferroptosis is considered as an important link between cellular stress and liver damage/progression. This article describes solute carrier family 7 member 11 (SLC7A11), the functional subunit of the cystine/glutamate antiporter, System Xc-, as a major context-dependent regulator of hepatic ferroptosis. SLC7A11 supports cystine uptake, GSH synthesis, and detoxification of lipid peroxides through glutathione peroxidase 4 (GPX4), which in turn provides protection from ferroptosis caused by different kinds of liver damage (drug-induced liver injury, ischemia/reperfusion injury, inflammation-induced liver damage, metabolic dysfunction-related fatty liver disease, and chronic toxic liver damage). At the same time, the effect of SLC7A11 on cells is also depended on the type of cell and stage of disease. For instance, in activated hepatic stellate cells, the prolonged action of SLC7A11 may lead to viability of cells boosting fibrosis, while blocking its activity will help induce ferroptosis and reduce fibrosis. In hepatocellular carcinoma, the elevated expression of SLC7A11, a protein that mediates antioxidant defense in cells, aids cancer cell survival and resistance to therapy. Thus, one conclusion that can be inferred from this review is that SLC7A11 could be viewed as a potential target of therapy in a pro-ferroptotic context. The evidence now available suggests that the best therapeutic strategy would involve targeting SLC7A11 differently in different cells. In hepatocytes, SLC7A11 could be promoted to improve cell viability whereas in affected fibrogenic or malignant cells it would need to be inhibited. Various agents are at hand for implementing such bidirectional regulation: pharmacological drugs, herbal remedies, stem cell-derived exosomes, nanomedicines, and genetic interventions. Unfortunately, cell type-specific delivery of substances remains a challenge and protection of cancer cells is also a possibility in this case.