Unifying mechanism for different fibrotic diseases

Area of Science:

• Fibrosis research
• Molecular biology
• Translational medicine

Background:

• Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and scleroderma, are poorly understood, have poor prognoses, and are currently incurable.
• Despite phenotypic differences, a common pathomechanism was suspected for diverse fibrotic conditions.

Purpose of the Study:

• To investigate the potential shared molecular mechanisms underlying various fibrotic diseases.
• To identify a central molecular mediator driving fibrotic conditions.

Main Methods:

• Analysis of fibrotic diseases including IPF, scleroderma, myelofibrosis, and organ-specific fibrosis.
• Induction of c-Jun in mouse models to assess fibrotic development.
• Single-cell mass cytometry to analyze signaling pathways activated by c-Jun.
• Testing therapeutic interventions targeting c-Jun-related pathways (αCD47 antibody, VEGF, PI3K inhibition).

Main Results:

• Multiple fibrotic diseases converge on the activation of the AP1 transcription factor c-JUN in pathological fibroblasts.
• FRA2 expression was specific to pulmonary artery hypertension.
• Sustained c-Jun induction in mice caused multi-organ fibrosis and steatohepatosis.
• c-Jun activation of pAkt and CD47 pathways was observed in both mouse models and human fibrotic diseases.
• αCD47 antibody treatment and inhibition of VEGF or PI3K reversed c-Jun-mediated fibrosis in vivo.

Conclusions:

• c-JUN acts as a central molecular mediator in most fibrotic conditions.
• Targeting c-JUN and its downstream signaling pathways (pAkt, CD47) presents a promising therapeutic avenue for fibrotic diseases.