Another breakthrough in the field of targeting ferroptosis to prevent and treat fatty liver disease

Recently, the research results of the collaborative research team of Professor Min Junxia and Professor Wang Fuyi of Zhejiang University were published in Science Bulletin as a cover article. The results of this study showed that the imbalance of non-essential amino acid metabolism mediated by liver SLC7A11 promotes the progression of MASLD disease, and ferroptosis caused by serine deficiency can become a new strategy for the treatment of MASLD.

The proposed model of the mechanism of SLC7A11-mediated fatty liver

Metabolic dysfunction-associated fatty liver disease (MASLD) has caused a heavy health and economic burden worldwide, so it is urgent to study its mechanism of action and develop effective targets. Non-essential amino acids are closely related to metabolic diseases. SLC7A11 is a functional subunit of the cystine-glutamate antiporter Xc-system. Cysteine ​​transferred into the cell is reduced to cysteine, which is further involved in the synthesis of glutathione GSH to maintain cellular redox homeostasis. Its role in metabolic dysfunction-associated fatty liver disease has not yet been fully revealed.

Through immunohistochemical analysis of SLC7A11 in human liver tissue, the researchers found that the expression of SLC7A11 was positively correlated with the severity of MASLD, but there were differences between each group of people, suggesting that the role of SLC7A11 in the development of MASLD may be more complex. In order to explore its specific function, the researchers first compared Slc7a11 knockout (Slc7a11-/-) mice and control mice fed with methionine choline-deficient diet (MCD), and found that the liver lipid accumulation and inflammation of the knockout mice were aggravated, and cysteine ​​and GSH/GSSG were significantly reduced. The use of the ferroptosis inhibitor Fer-1 can significantly protect the progression of fatty liver, suggesting that the knockout mice promote the development of MASLD through the classic ferroptosis pathway.

Loss of Slc7a11 in mice exacerbates diet-induce MASLD via ferroptosis

To further explore the role of SLC7A11 in MASLD, the researchers constructed liver-specific overexpression (Slc7a11-LTG) mice. After modeling with MCD, HFD, and Western Diet+CCl4, the progression of MASLD in Slc7a11-LTG mice was accelerated compared with control mice. In addition, this finding was also confirmed using the Pten liver-specific knockout mouse model. Specifically, after overexpression of Slc7a11, its transport capacity was enhanced, cystine increased and glutamate decreased in hepatocytes; however, cysteine ​​was also significantly reduced, and GSH/GSSG decreased. This phenotype has attracted special attention from researchers.

Overexpressing Slc7a11 promotes hepatic steatosis in HFD-induced MASLD via ferroptosis.

In order to find out the reason for the "abnormality" of Slc7a11, the researchers used transcriptomics and non-targeted metabolomics to find that the amino acid metabolic pathway of Slc7a11-LTG mice after modeling was significantly changed; further screening and locking serine through amino acid targeted metabolomics and mouse in vitro liver primary cell experiments. Next, the researchers explored how serine affects cysteine ​​to mediate ferroptosis. Previous studies have shown that an important source of cysteine ​​is the synthesis of serine through the transsulfurization pathway. In vitro, the researchers used cystathionase (CTH) inhibitors to block the transsulfurization pathway and metabolic flow experiments to prove that glutamate-derived serine in Slc7a11-overexpressing hepatocytes was significantly reduced, promoting ferroptosis; at the same time, in mouse modeling experiments, Slc7a11-LTG mice supplemented with serine or used ferroptosis inhibitors can reduce lipid peroxidation and improve MASLD. These results suggest that the reduction of serine leads to a reduction in cysteine ​​synthesized through the transsulfurization pathway, thereby mediating ferroptosis under modeling conditions.

Glutamate deficiency-induced serine deficiency underlies the progression of MASLD in mice overexpressing Slc7a11.

In addition, the serum serine/glutamate ratio decreased significantly in multiple mouse models. Using a population cohort for meta-analysis, researchers found that serum serine was significantly reduced in MASLD patients, while serum glutamate tended to increase. These suggest that the serum serine/glutamate ratio has the potential to serve as a biomarker for MASLD.

Summary of achievements:

It is the first report that SLC7A11 can mediate serine metabolism balance and regulate the occurrence of MASLD;

It was first revealed that abnormal metabolism of non-essential amino acids such as serine, cysteine ​​and glutamate mediated by liver SLC7A11 is an important mechanism that triggers MASLD;

Supplementing serine to block ferroptosis may become a new strategy for treating MASLD;

Serum serine/glutamate ratio is expected to become a biomarker for the diagnosis and treatment of MASLD.

For more details, please read the full article

Essentiality of SLC7A11-Mediated Nonessential Amino Acids in MASLD. Science Bulletin. doi:10.1016/j.scib.2024.09.019