Newswise — LOS ANGELES (Oct. 30, 2024) -- New research led by Cedars-Sinai investigators has reversed liver fibrosis, a gradual buildup of scar tissue in the liver, in laboratory mice. Their achievement marks a crucial step toward potentially creating new treatments for patients with this condition, which can lead to life-threatening diseases including cirrhosis, liver failure and liver cancer.
Liver fibrosis can be triggered by many factors, including viruses that cause hepatitis (infection and inflammation in the liver), long-term alcohol use or some metabolic disorders. Because it produces few or no symptoms at first, the condition typically progresses slowly for years, going undetected until it has caused serious organ damage. At that stage, liver transplantation may be the only effective treatment. The ability to undo the scarring would be a major breakthrough for patient care.
In their study, published in the peer-reviewed journal Nature Communications, Cedars-Sinai investigators examined three genes and the proteins that they made. One of them, FOXM1, is known to cause liver cancer, inflammation and fibrosis when it becomes overactive in hepatocytes, a type of liver cell. The two other genes, MAT2A and MAT2B, are required to activate another type of cell, hepatic stellate cells, which plays a key role in liver fibrosis. The study demonstrated that the proteins coded by these three genes interact and that all three are needed to produce liver fibrosis.
“We discovered that these proteins ‘talk’ with each other inside liver cells,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and corresponding author of the study. “They even influence nearby cells through extracellular vesicles—fat molecules filled with genetic fragments, proteins and other biological materials that act as messengers between cells. Working together, that is how these proteins stimulate each other, driving liver inflammation and fibrosis.”
These discoveries raised the possibility that inactivating just one of the three proteins might block liver fibrosis. To test that theory, the team induced liver inflammation and fibrosis in laboratory mice and treated them with a substance known as FDI-6 that blocks the FOXM1 protein. In a series of experiments, they showed that FDI-6 could prevent liver fibrosis from developing, halt further progression and even reverse the condition, resulting in the scarring disappearing.
Although both mice and humans have all three genes, and these genes also are more highly expressed in human liver fibrosis and cirrhosis, the study did not prove that a similar treatment would work in patients with liver fibrosis. Reaching that conclusion would require additional research and testing, Lu said.
“What we achieved was to unveil the axis of FOXM1, MAT2A and MAT2B as a potential target for developing drugs to treat liver fibrosis,” Lu said. “Our findings suggest that blocking any of these proteins might be useful in treating this condition.”
Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, “This highly original study significantly advances our understanding of an insidious condition that too often leaves patients and doctors with few treatment options. It is emblematic of Cedars-Sinai’s innovative scientific work.”
Other Cedars-Sinai authors include Bing Yang, Liqing Lu, Ting Xiong, Wei Fan, Jiaohong Wang, Lucía Barbier-Torres, Jyoti Chhimwal, Sonal Sinha, Takashi Tsuchiya, Nirmala Mavila, Maria Lauda Tomasi, DuoYao Cao, Jing Zhang, Hui Peng, Komal Ramani, Jenny Han, Ekihiro Seki and Heping Yang. Additional authors include Jose M. Mato, Ting Liu, Xi Yang and Vladimir V. Kalinichenko.
Funding was provided by the National Institutes of Health grant P01CA233452 to S.C. Lu, H. Yang and E. Seki; Plan Nacional of I + D SAF2017-88041-R to J.M. Mato; and the National Natural Science Foundation of China 82070632 to Liu T.
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