A multidisciplinary and international study has revealed the decisive contribution of cathepsin B to the progression of alcoholic hepatitis, a serious disease affecting millions of people worldwide and one of the main causes of alcohol-related liver damage. The work, carried out by the University of California in San Diego in collaboration with the University of Seville and fifteen other institutions from the United States, Germany, the Netherlands and Japan, has identified this enzyme as the key protein in the development of the disease.
The findings have been published in the Journal of Hepatology, a leading journal in liver research, and represent a key advance in understanding the role of cathepsin B, which until now was poorly understood. “Identifying the molecular details of the causal agents involved in the progression of alcoholic hepatitis brings us closer to designing effective treatments, which so far have not been developed,” explains Professor Irene Díaz-Moreno from the University of Seville, at the Institute of Chemical Research, within the Isla de la Cartuja Scientific Research Center (IIQ-cicCartuja, US-CSIC).
In the study, proteins present in fecal samples from 119 patients from five centers in America and Europe were analyzed: 80 with alcoholic hepatitis, 20 with alcohol use disorder, and 19 healthy controls. The results showed that cathepsin B levels progressively increase in patients with alcohol use disorder (AUD) and alcoholic hepatitis compared to controls, and that these elevated levels are associated with higher mortality.
Furthermore, experiments in mouse models exposed to alcohol demonstrated that hepatic macrophages are responsible for expressing and secreting cathepsin B. Once released, the enzyme reaches the intestine, where it degrades proteins that maintain the integrity of the intestinal epithelium. The weakening of this barrier facilitates the passage of bacterial toxins to the liver, promoting the progression of liver damage. Genetic deletion of cathepsin B in macrophages or its inactivation using a specific inhibitor prevented this degradation and reduced the associated damage.
The Biointeractomics group at the University of Seville contributed to elucidating, through computational methods and molecular modeling, the structural mechanisms by which cathepsin B recognizes and degrades proteins of the intestinal epithelium, as well as characterizing how its specific inhibitor blocks the interaction at the atomic level. The results obtained will enable the development of new therapeutic strategies to block the action of cathepsin B.
Overall, the research provides a comprehensive view of the mechanism linking chronic alcohol consumption with disruption of the intestinal barrier and the progression of liver disease, and identifies cathepsin B as a key causal factor in alcoholic hepatitis, a condition that currently has limited therapeutic options.
Bibliographic reference:
Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2026.01.013
