Fibrosis (overgrowth of scarred fibrous connective tissue) contributes to 45% of deaths in Western countries and currently has no specific treatment. A new work, led by a team from the CSIC's Barcelona Biomedical Research Institute, identifies the role of the protein cathepsin D in the degradation and remission of fibrotic tissue, which opens up new possibilities for medical treatment

Cathepsin D expression (green) in macrophage populations (blue and red) during liver fibrosis. Credit: María Fernández, IIBB-CSIC.

Fibrosis or overgrowth of fibrous connective tissue in an organ or tissue contributes to 45% of deaths in Western countries. Fibrosis can occur in a multitude of organs in the body and occurs when the normal healing process is disrupted and functional tissue is progressively replaced by scar or fibrous tissue.

As Anna Moles, a researcher at the  Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC) associated with IDIBAPS and CiberEHD, explains, ‘if the healing process is deregulated, excessive growth of scar tissue means less functional tissue, which leads to organ malfunctioning that may result in the need for a transplant. In addition, fibrosis predisposes to the development of other pathologies such as cancer’.

Moles is head of the ‘Tissue Remodelling, Fibrosis and Cancer’ research group at the IIBB-CSIC, which studies new strategies for the treatment of fibrosis. In the case of liver fibrosis, which is largely reversible, she explains, her team studies which mechanisms are related to fibrosis reversal, in search of new therapeutic options.

Now, a study published this month in the journal Molecular Metabolism and led by Anna Moles, proposes a new treatment pathway based on a protein, cathepsin D, expressed by macrophages during liver fibrosis.

‘Cathepsin D,’ explain Paloma Ruiz, María Fernández and Valeria Pistorio, first authors of the study, ’is a protein that is expressed in the lysosomes - organelles that degrade excess or surplus cellular debris - of macrophages. Our work aims to exploit the degradative capacity of macrophage lysosomes to degrade fibrotic tissue and restore the normal balance of the organ.

In the study, carried out with cell cultures and murine models, they have observed that when cathepsin is present there is a remission of fibrosis. In contrast, when cathepsin D expression is suppressed in the macrophage, fibrotic tissue degradation does not occur, perpetuating and aggravating fibrosis.

In parallel, the group has analysed RNA-sequenced datasets of cells from patients with cirrhosis and confirmed that a group of macrophages with scar-degrading characteristics have high expression of the protein cathepsin D. This finding confirms that this is a molecule that is present in scar-degrading macrophages and could play an important role in the resolution of this pathology. This finding would confirm that this is a molecule that is present in degradative macrophages and could play an important role in the resolution of this pathology.

Liver fibrosis currently lacks a specific treatment. Previous unsuccessful attempts at drug development have so far focused on preventing scar deposition. In contrast, this latest research is based on exploiting the scar-degrading potential of macrophages. The result opens up new possibilities for the development of liver fibrosis treatments based on this degradation potential.

On the one hand, one could consider modulating cathepsin D, boosting its expression in macrophages when necessary. On the other hand, if it is not possible to control cathepsin D expression, adds Anna Moles, ‘another strategy would be to study the “partner” molecules of cathepsin D, which cooperate with it in this degradative function within the macrophage to design drugs that target these proteins to amplify the degradation of the scars and thus reverse fibrosis and improve liver function’.

Researchers from the University of Barcelona, IDIBAPS, the University Hospital of Valdecilla-IDIVAL, the University of Naples Federico II (Italy); the Centre de Recherche Saint-Antoine (CRSA) (France); the Biotech Research and Innovation Centre (BRIC) (Denmark); the USC Research Center for ALPD (USA) and the Albert-Ludwigs-University and the Center for Biological Signaling Studies BIOSS, University of Freiburg (Germany) are also participating in the study.

This work has been funded thanks to several projects and contracts with the Ministry of Science and Innovation, the Ministry of Universities and the CSIC, as well as a project with the company Pfizer.

This work has been funded thanks to the Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033/FEDER, EU (projects: PID2021-123652OB-I00, RTI2018-097475-A-100 and contracts: RYC-2016-19731 and PRE2022-101676), Pfizer (project: #77131383), the Ministry of Universities (contracts: FPU19/05357 and FPU20/01367) and CSIC (contract: JAEINT_23_0124).

Reference article:

Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis Paloma Ruiz-Blázquez, María Fernández-Fernández, Valeria Pistorio, Celia Martinez-Sanchez, Michele Costanzo, Paula Iruzubieta, Ekaterina Zhuravleva, Júlia Cacho-Pujol, Silvia Ariño, Alejandro Del Castillo-Cruz, Susana Núñez, Jesper B. Andersen, Margherita Ruoppolo, Javier Crespo, Carmen García-Ruiz, Luigi Michele Pavone, Thomas Reinheckel, Pau Sancho-Bru, Mar Coll, José C. Fernández-Checa, Anna Moles.  Molecular Metabolism Volume 87, September 2024, 101989. https://doi.org/10.1016/j.molmet.2024.101989