A new study published in International Immunopharmacology provides a basis for considering the use of all-trans retinoic acid (ATRA), a metabolite of vitamin A and a first-generation natural retinoic acid, in the treatment of  systemic sclerosis (SSc).

In addition, the study confirmed the profibrotic effect of the transcription factor fos-related antigen 2 (Fra2) in SSc, highlighting it as a potential target for antifibrotic therapies.

“Fra2 and ATRA could serve as therapeutic targets and potential therapeutic agents for the treatment of multiorgan fibrosis in SSc, respectively, thus offering new possibilities for the treatment of SSc,” the study’s authors concluded.

The researchers observed increased levels of Fra2 in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals. Inhibition of Fra2 expression in SSc dermal fibroblasts using Fra2 small interfering RNA (siRNA) markedly reduced the expression of collagen I, a marker of fibrosis.

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Furthermore, ATRA decreased the expression of Fra2, collagen I, and α-smooth muscle actin in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals. Further experiments demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity.

By using 2 distinct databases, the researchers identified potential binding sites for the transcription factor RARα in the promoter region of the FRA2 gene.

Altogether, these findings suggest that ATRA reduces collagen I expression both in vitro and in vivo by downregulating Fra2 expression.

The anti-inflammatory, antiproliferative, and antifibrotic properties of ATRA have been established in recent research. However, the exact mechanism behind these effects is not fully understood.

ATRA is a commonly used clinical treatment that has been extensively studied for various diseases, including cancer and inflammatory conditions. Its proven safety and efficacy have made it a popular subject of research. Previous studies and recent research, including this study, have demonstrated that ATRA holds promise as a treatment for SSc, including in addressing cutaneous and pulmonary fibrosis.


Pi Z, Liu J, Xiao Y, et al. ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis. Int Immunopharmacol. Published online June 16, 2023. doi:https://doi.org/10.1016/j.intimp.2023.110420