Researchers at King's College London have demonstrated that cyclophilin inhibitors can reverse key features of alcohol-related liver disease by fundamentally altering the structural composition of damaged liver tissue. The breakthrough study, published in the British Journal of Pharmacology, used laboratory-grown three-dimensional models derived from human liver tissue to explore how these drugs combat fibrosis—a progressive condition that causes liver tissue to become stiff and functionally impaired.
The research addresses a significant unmet medical need, as there are currently no approved medical therapies for treating fibrosis caused by alcohol-related liver disease. Fibrosis develops when repeated liver injury leads to the replacement of normal tissue with scar tissue, impairing the liver's flexibility and function and potentially resulting in irreversible organ damage if left untreated.
Novel Human Tissue Models Reveal Drug Mechanisms
The research team, led by the Roger Williams Institute of Liver Studies at King's College London, 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, providing clinically relevant material for investigation.
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 that normally contribute to the structural stiffness characterizing fibrotic tissue. Molecular analyses revealed that the drug reduced the expression of genes involved in fibrosis pathways.
In the second model, researchers isolated hepatic stellate cells—the primary fibrogenic cell type in the liver that becomes activated in response to injury. These cells were chemically stimulated 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.
Targeting Cyclophilins Shows Dual Therapeutic Effect
The study focused on cyclophilins, a family of proteins previously implicated in driving fibrosis in various types of liver injury. While early-stage clinical studies have explored cyclophilin inhibitors in other forms of liver disease, their mechanisms of action in alcohol-related contexts were not well understood until now.
The two experimental models demonstrated that cyclophilin inhibitors can both prevent the accumulation of fibrotic proteins and modify the architecture of liver tissue damaged by alcohol exposure. This dual mechanism provides new insight into how these drugs function at cellular and molecular levels in human tissues.
Clinical Relevance Through Human-Derived Models
The use of human-derived models gives the study exceptional 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 experimental work was carried out by Una Rastovic, a doctoral researcher, and Dr. Sara Campinoti, a postdoctoral scientist. The study was funded by the Foundation for Liver Research and Hepion Pharmaceuticals, highlighting industry interest in developing cyclophilin inhibitors for liver disease applications.
The findings suggest that cyclophilin inhibitors could potentially enable the liver to remodel itself toward a healthier state by halting the build-up of proteins that contribute to tissue stiffness. This research provides a foundation for advancing cyclophilin inhibitors toward clinical trials specifically targeting alcohol-related liver fibrosis.
