Recently, Professor Chuan Su’s team from the School of Basic Medical Sciences, Nanjing Medical University (NMU) published a research paper titled “Epigenetic repression of hepatocyte FoxO1 disrupts local immune homeostasis and promotes liver inflammation” in Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). This study is the first to reveal that hepatocyte FoxO1 plays a critical role in maintaining liver immune homeostasis. In various liver diseases, including schistosomiasis-related liver disease and alcoholic liver disease, FoxO1 undergoes epigenetic repression, thereby promoting liver inflammation and fibrosis progression. These findings provide new insights into the mechanisms underlying liver inflammation and fibrosis and identify a novel therapeutic target for future clinical intervention of liver diseases.
Globally, approximately 2 million people die from liver diseases each year, and liver inflammation is a key pathogenic factor common to nearly all forms of liver disease. In recent years, the regulatory role of hepatocytes in shaping the liver immune microenvironment has received increasing attention. During the progression of acute and chronic liver diseases caused by infections or other factors, hepatocyte damage and the resulting disruption of immune homeostasis significantly contribute to liver inflammation and fibrosis. However, the molecular mechanisms underlying these processes remain incompletely unuderstood.
Previous research by the team revealed that the hepatocyte surface molecule CD1d exerts dual hepatoprotective effects by inhibiting hepatocyte apoptosis and controlling liver inflammation (National Invention Patent: A surface molecule that inhibits hepatocyte apoptosis and its application; Inventors: Chuan Su, Sha Zhou, Zhigang Lei, Xiaojun Chen; Patent No. ZL202211307543.9, granted in August 2025). In liver diseases such as schistosomiasis-related liver disease and fatty liver disease, CD1d expression is severely downregulated in a "cliff-like" manner, thereby accelerating liver inflammation and fibrosis progression (Lei ZG et al., Immunology, 2021; Lei ZG et al., Journal of Hepatology, 2024). Nevertheless, the mechanism underlying this phenomenon remained unknown.
In the present study, the research team conducted in-depth screening of gene expression profiles within the liver tissue microenvironment of patients with various liver diseases, including schistosomiasis-related and alcoholic liver diseases. They identified a common suppression of the hepatocyte epigenetic regulator JMJD1C, which encodes a histone demethylase. This suppression led to increased H3K9me2 methylation at the promoter region of the Foxo1 gene, resulting in transcriptional repression and downregulation of Foxo1 expression. Consequently, retinoic acid metabolism in the liver was disrupted, leading to decreased expression of the hepatoprotective molecule CD1d and promoting liver inflammation and fibrosis.
The co-first authors of this paper are Zhigang Lei (postdoctoral researcher), Yu Wu (Ph.D.), Weijie Xue (Ph.D.) from the School of Basic Medical Sciences, NMU, and Dr. Dongmei Zhu from the Liver Disease Center of Changzhou Third People's Hospital. The co-corresponding authors are Professor Chuan Su, Professor Sha Zhou, Professor Xiaojun Chen from the School of Basic Medical Sciences, as well as Professor Chunyan Ye from the Liver Disease Center of Changzhou Third People's Hospital. This research was supported by the National Natural Science Foundation of China (Key and General Programs), the Natural Science Foundation of Jiangsu Province, the Changzhou Medical Center Key Project, and the China Postdoctoral Science Foundation.
Original article link:
(Drafted by Professor Chuan Su’s research team; Reviewed by Chuan Su and Juejin Wang; Translation reveiwed by Bei Zhang )
