Fibrosis is the buildup of connective tissue in various organs. Found in most chronic diseases, it is associated with disease progression and is responsible for 45% of all deaths in industrialised countries. Whereas the liver is one of the primary organs affected, the heart and kidneys are also significantly affected.
The cells responsible for generating fibrosis in the liver are known as stellate cells. These cells are normally at rest, but when there is damage to body tissues, they are activated and secrete connective tissue to repair it. Fibrosis occurs when these stellate cells are overactivated.
Now, a team from IDIBAPS-Hospital Clínic has published an article in the journal Nature Communications describing how stellate cells form and adopt their functional characteristics. In this process, they identify that the transcription factor RORA regulates the activation of stellate cells, regulating fibrosis in the liver, heart and kidneys. Led by Pau Sancho-Bru, the team of researchers have demonstrated that RORA prevents the uncontrolled activation of stellate cells, modulating their metabolic state and blocking the appearance of fibrosis.
According to Pau Sancho-Bru, the head of the IDIBAPS research group Liver cell plasticity and tissue repair: ‘This information is key to improving our understanding of disease progression and to developing more effective therapies. In fact, our results show the potential of RORA as an antifibrogenic therapeutic target in different organs’.
The importance of understanding the pathways of cell differentiation
Once embryonic development ends, during which stem cells differentiate into all the cell types that make up the body’s tissues, homeostasis processes begin. In these processes, the signalling pathways that were active during development can be reactivated to maintain or repair adult tissue.
For this study, a technology previously developed in the laboratory that enables the transformation of pluripotent stem cells into hepatic stellate cells was combined with transcriptomics and proteomics techniques to analyse the molecular and functional changes during the process. This approach led to the identification of RORA as a key player in the process, which not only plays an important role in the early stages of embryonic development, but also regulates the activation of stellate cells in response to damage in adults.
‘Our study stresses the importance of examining cellular trajectories, both during differentiation and in disease. This allows us to identify key proteins in the fibrosis process that can lead to the development of new therapeutic strategies’, says Raquel Martínez, an IDIBAPS researcher and the first author of the study.
RORA as a key player in animal and human models
The research team conducted studies on the role of RORA in both animal and human models. On the one hand, they observed that mice lacking RORA expression showed increased fibrosis in the liver, kidneys and heart. On the other hand, when this lack of expression was compensated by administering RORA exogenously, multiorgan fibrosis was reversed.
In human in vitro models, the exogenous administration of RORA also reduced fibrosis in body tissues. Furthermore, the more fibrosis that patients with liver disease had, the lower the expression of RORA.
Reference article
Martínez García de la Torre, R.A., Vallverdú, J., Xu, Z. et al. Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis. Nat Commun 16, 1489 (2025). https://www.nature.com/articles/s41467-025-56024-4#citeas
