The nuclear receptor DAX1 regulates WNT signaling to promote fibroblast activation and skin fibrosis in systemic sclerosis

• Applicant: Dr. Yun Zhang
• Subject Area: Rheumatology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572826818

Fibrotic diseases contribute to up to 45% of deaths in the developed world and impose a major socioeconomic burden on modern societies. Fibrotic diseases are associated with high morbidity and mortality rate and are thus considered as one of today´s major health care challenges. Fibrotic diseases are characterized by an accumulation of myofibroblasts, which release excessive amounts of extracellular matrix. Although key factors of fibroblast activation have been identified, the molecular mechanisms underlying the persistent activation of myofibroblasts in fibrotic disease are incompletely understood. We demonstrate in our preliminary results that DAX1 expression is upregulated in SSc and in murine models of fibrosis, that DAX1 expression is regulated in a TGFβ-dependent manner. Furthermore, inactivation of DAX1 prevents myofibroblast differentiation and inhibits the release of collagen in vitro in fibroblasts cultured under standard conditions as well as in full thickness skin models. Moreover, knockdown of DAX1 ameliorates bleomycin-induced and cGvHD-induced dermal fibrosis. With the current proposal, we aim to characterize the molecular mechanisms of the profibrotic signaling pathways in detail and further validate DAX1 as a potential target for antifibrotic therapies. We plan to analyze DAX1 expression in different cellular players of other fibrosing disease such as cGvHD and hypertrophic scar patient’s skin in situ by IMC. To identify the DAX1 regulated genes on fibroblast-to-myofibroblast transition using multi-omics approaches and characterize the functions of different domains of DAX1 using CRISPR-Cas9. Finally, to better correlate with clinical application, we plan to evaluate the effect of DAX1 inactivation by its antagonist BPK-29 in precision cut slices of SSc skin. Our application may thus establish DAX1 as a novel target for antifibrotic therapies.

• DFG Programme: Research Grants