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USC CiMUS researchers find a potential therapeutic target to combat liver fibrosis, the leading cause of liver transplants

  • It is a mechanism involved in the development of this disease in patients with fatty liver disease, which consists of inhibiting the p63 protein in certain liver cells.
  • The discovery, published in the prestigious scientific journal Cell Reports Medicine, is essential in the approach to this pathology that usually leads to cirrhosis and for which, until now, there is no treatment.

Liver fibrosis is a chronic disease that manifests itself in advanced stages of fatty liver, is on the verge of cirrhosis and, for the moment, has no treatment, making it the leading cause of liver transplantation. Now, researchers from the CiMUS of the University of Santiago de Compostela (USC) in the group led by Rubén Nogueiras have taken a new qualitative leap forward in this field by discovering a possible therapeutic target by inhibiting the p63 protein, which is essential for certain liver cells to activate their metabolism during fibrosis.

By inactivating this protein in various preclinical models, the researchers have also succeeded in reducing inflammation in the liver. "We are very pleased to have found a target that could be the focus of future studies aimed at developing new drugs to tackle liver fibrosis," say Marcos Fernández Fondevila and Eva Nóvoa Deaño, lead authors of the article. The work has just been published in Cell Reports Medicine, one of the most relevant international journals in this area of research.


Liver fibrosis, dangerous scars

Liver fibrosis is an increasingly common disease, mainly due to the growing number of people with obesity and type 2 diabetes, two of the pathologies most associated with so-called fatty liver disease, which can lead to fibrosis. Once it appears, lifestyle changes are not enough to halt or reverse it, and there is, for the moment, no approved drug for its treatment. Such is the situation that metabolic liver fibrosis has now become the most common cause of liver transplants and multiplies the risk of patient mortality.

As part of a research line launched at CiMUS several years ago, the study shows that patients with fibrotic fatty liver disease have elevated levels of the p63 protein, particularly in the liver's stellate cells. The main function of these cells is to store vitamin A under normal conditions. In addition, they play an important role in liver tissue repair. In particular, in response to damage or inflammation in the liver, the stellate cells activate their metabolism, consuming a large amount of nutrients and producing energy that they use to produce the collagen fibres we know as scars. When this process gets out of control, as it does in some patients with fatty liver disease, large scar septa are produced, preventing the liver from functioning properly. This phenomenon is known as liver fibrosis.

"In our group at USC CiMUS, we have found that p63 is essential for stellate cells to activate their metabolism during fibrosis. By inhibiting p63 in these cells, we can limit them from obtaining energy and consequently reduce fibrosis production," say Fernández Fondevila and Nóvoa Deaño. They add that "by inhibiting p63, the cells are unable to activate HER2, which is widely known to play a role in the development of some types of cancer". Furthermore, "we have not only managed to reduce liver fibrosis, but also to reduce inflammation in the liver by inactivating p63, using various preclinical models. This achievement has allowed us to identify a specific therapeutic target that could open the door to future research aimed at the discovery of specific drugs".

This work is the result of a multidisciplinary collaboration led from the CiMUS group of the USC by Rubén Nogueiras Pozo, Oportunius researcher and professor at the USC, and in which other CiMUS research teams (Carlos Diéguez, Román Pérez, Ashwin Woodhoo and Marta Varela) have participated, the Marqués de Valdecilla University Hospital (Javier Crespo and Paula Iruzubieta) and groups from the National Centre for Cardiovascular Research and the Complutense University of Madrid, CIC bioGUNE in Bilbao, the University Hospital of Salamanca and Columbia University in New York.