In patients with diffuse cutaneous systemic sclerosis (SSc), inhibitors such as the Tripterygium wilfordii derivative celastrol have been shown to block the ways in which cells perceive matrix stiffness and thus may be beneficial in alleviating skin fibrosis.
A pharmacokinetic study on the subject was conducted in patients with diffuse cutaneous SSc, with the findings published in Annals of the Rheumatic Diseases.
Among individuals with the autoimmune connective tissue disorder SSc, progressive fibrosis of the skin and internal organs is observed, which can be associated with considerable organ dysfunction and mortality. Based on the transcriptional coactivator yes activated protein-1 (YAP1) being recognized as a major downstream effector of mechanotransduction, YAP inhibitors may play a therapeutic role in the treatment of SSc-associated fibrosis.
Although the terpenoid celastrol is a YAP inhibitor, whether celastrol can alleviate SSc-related fibrosis remains to be elucidated, with the cell niches necessary for cutaneous fibrosis still unknown. In the current pharmacokinetic study, the researchers evaluated the ability of celastrol to antagonize transforming growth factor beta (TGFβ) activation of human dermal fibroblasts; reduce the persistent fibrotic phenotype of lesional SSc fibroblasts; and avert the development of bleomycin-generated skin fibrosis.
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They treated human dermal fibroblasts from healthy individuals and from participants with diffuse cutaneous SSc with or without TGFβ, with or without celastrol. In addition, mice were exposed to the bleomycin-induced model of skin SSc with or without celastrol. The evaluation of fibrosis was performed through RNA sequencing, real-time polymerase chain reaction, spatial transcriptomic analyses, enzyme-linked immunosorbent assay, Western blot, and histologic examination.
A group of 2073 celastrol-sensitive genes were identified and underwent functional analysis. Results demonstrated that celastrol selectively inhibited those genes that were expected to be involved in the following:
- Extracellular space
- Extracellular matrix
- TGFβ signaling
- Hippo signaling
- Focal adhesion kinase/phosphatidylinositol 3-kinase/Akt signaling
- Notch signaling
- Janus kinase-signal transducer and activator of transcription signaling
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Study findings reported that in dermal fibroblasts, celastrol weakened the power of TGFβ to generate an SSc-like pattern of gene expression, such as the cellular communication network factor 2, TGFβ1, and collagen I. Further, celastrol lessened the persistent fibrotic phenotype of dermal fibroblasts that had been cultured from the cells of patients with SSc.
In the bleomycin-induced model of skin SSc, an elevated expression of genes related to hippo/YAP and reticular fibroblast clusters was seen. In contrast, celastrol inhibited nuclear localization of YAP and blocked the bleomycin-generated changes.
“Our data provide new and valuable insights into the molecular mechanisms underlying SSc fibrosis and suggest that inhibitors of YAP1, such as celastrol, require clinical attention,” the investigators explained. “Compounds, such as celastrol, that antagonize the YAP pathway may represent potential treatments for SSc skin fibrosis,” they concluded.
Chitturi P, Xu S, Abdi BA, et al. Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis. Ann Rheum Dis. Published online June 16, 2023. doi:10.1136/ard-2023-223859