Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis

ObjectivesSystemic sclerosis (SSc) is characterised by extensive tissue fibrosis maintained by mechanotranductive/proadhesive signalling. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol is a YAP1 inhibitor; however, if celastrol can alleviate SSc fibrosis is unknown. Moreover, the cell niches required for skin fibrosis are unknown. MethodsHuman dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor beta 1 (TGF beta 1), with or without celastrol. Mice were subjected to the bleomycin-induced model of skin SSc, in the presence or absence of celastrol. Fibrosis was assessed using RNA Sequencing, real-time PCR, spatial transcriptomic analyses, Western blot, ELISA and histological analyses. ResultsIn dermal fibroblasts, celastrol impaired the ability of TGF beta 1 to induce an SSc-like pattern of gene expression, including that of cellular communication network factor 2, collagen I and TGF beta 1. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of skin SSc, increased expression of genes associated with reticular fibroblast and hippo/YAP clusters was observed; conversely, celastrol inhibited these bleomycin-induced changes and blocked nuclear localisation of YAP. ConclusionsOur data clarify niches within the skin activated in fibrosis and suggest that compounds, such as celastrol, that antagonise the YAP pathway may be potential treatments for SSc skin fibrosis.

Automated summary

It has been discovered that the mechanosensitive transcriptional co-activator YAP1 is activated in fibroblasts of systemic sclerosis (SSc). Additionally, the YAP1 inhibitor celastrol has been found to alleviate fibrosis in SSc fibroblasts. Furthermore, cell niches required for skin fibrosis have also been identified. These findings provide potential targets and strategies for the treatment of SSc skin fibrosis.