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A study conducted by researchers at King’s College London has found that a class of drugs known as cyclophilin inhibitors can reverse key features of alcohol-related liver disease by altering the structural composition of liver tissue. The research used laboratory-grown three-dimensional (3D) models derived from human liver tissue to explore how the drugs act on fibrosis—a process that causes liver tissue to become stiff and functionally impaired.
Fibrosis is a hallmark of progressive liver damage, including damage caused by long-term alcohol use. It develops when repeated liver injury leads to the replacement of normal tissue with scar tissue. The accumulation of scar tissue impairs the liver’s flexibility and function and can result in irreversible organ damage if left untreated.
Despite its prevalence, there are no approved medical therapies for treating fibrosis caused by alcohol-related liver disease. In this study, the team focused on the role of a family of proteins known as cyclophilins, which have previously been implicated in driving fibrosis in various types of liver injury. Early-stage clinical studies have explored the use of cyclophilin inhibitors in other forms of liver disease, but their mechanisms of action in alcohol-related contexts were not well understood.
Human-derived models used to mimic disease progression
To investigate this, the researchers developed two experimental models using human liver tissue obtained from patients undergoing surgical procedures at King’s College Hospital NHS Foundation Trust. All samples were taken from non-tumor regions of the liver.
The first model involved precision-cut liver slices exposed to alcohol in the laboratory, simulating the type of cellular stress and tissue remodeling seen in alcohol-related liver damage. When treated with a cyclophilin inhibitor, the tissue exhibited reduced accumulation of fibrotic proteins. These proteins normally contribute to the structural stiffness that characterizes fibrotic tissue. Molecular analyses of these samples showed that the drug reduced the expression of genes involved in fibrosis pathways.
In a second model, the team isolated hepatic stellate cells from the same liver samples. Stellate cells are the primary fibrogenic cell type in the liver, becoming activated in response to injury. These cells were chemically stimulated in the laboratory to mimic their activated state, and then treated with the cyclophilin inhibitor. The treatment altered the type and organization of structural proteins these cells produced, effectively reducing their fibrogenic activity.
Together, the two models demonstrated that cyclophilin inhibitors can both prevent the accumulation of fibrotic proteins and modify the architecture of liver tissue damaged by alcohol exposure. These findings provide new insight into how these drugs function at a cellular and molecular level in human tissues.
Research highlights translational potential of human tissue models
The use of human-derived models gives the study a high level of clinical relevance, which is often lacking in preclinical studies based on animal models or immortalized cell lines. Access to surgically resected tissue enabled the team to study disease mechanisms in a setting that closely mirrors real-world disease progression in humans.
The study was led by researchers from the Roger Williams Institute of Liver Studies at King’s College London and funded by the Foundation for Liver Research and Hepion Pharmaceuticals. The experimental work was carried out by Una Rastovic, a doctoral researcher, and Dr Sara Campinoti, a postdoctoral scientist.
The results have been published in the British Journal of Pharmacology.
Reference: Rastovic U, Campinoti S, Wei L, et al. Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis. Br J Pharmacol. 2025. doi: 10.1111/bph.70139
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