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

Abstract

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 β1 (TGFβ1), 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 TGFβ1 to induce an SSc-like pattern of gene expression, including that of cellular communication network factor 2, collagen I and TGFβ1. 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.

Knockout of C1q/tumor necrosis factor-related protein-9 aggravates cardiac fibrosis in diabetic mice by regulating YAP-mediated autophagy

“…During Hippo pathway inactivation, YAP undergoes dephosphorylation and translocates to the nucleus, where it activates genes that drive its biological roles ( Kiang et al, 2024 ). Elevated YAP expression is a common feature of fibrosis in various organs, including pulmonary, hepatic, and renal fibrosis, and has been increasingly associated with cardiac pathologies ( Stancil et al, 2021 ; Zhang J. et al, 2023 ; Chitturi et al, 2023 ). YAP activation results in myocardial hypertrophy and fibrosis ( Garoffolo et al, 2022 ; Kashihara et al, 2022 ).…”

The role of yes activated protein (YAP) in melanoma metastasis

“…Celastrol acts as an antifibrotic agent and exhibits significant broad-spectrum anticancer activities. 90 , 91 , 92 Celastrol blocks proliferation of melanoma cells in vitro and in vivo and metastasis in mouse models, associated with impairment of adhesive signaling. 93 , 94 , 95 , 96 Celastrol also has antitumor activity in C57BL/6 mice bearing B16F10 tumors by both inhibiting tumor growth and increasing CD8 + T cells tumor penetration.…”

“…97 The activity of celastrol is also associated with reduced CCN1 and CCN2 expression. 91 , 98 Although poor water solubility and toxicity have limited the clinical potential of celastrol, much effort is being expended to circumvent these issues; for example, through the development of nanoparticle delivery systems. 99 …”

Skin Gene Expression Profiles in Systemic Sclerosis: From Clinical Stratification to Precision Medicine

“…In a bleomycin-induced model of SSc skin, Chitturi and colleagues [ 34 ] identified, by spatial transcriptomics based on cellular location within the skin and cell cluster analysis, four cellular niches (epithelia, papillary, reticular. or universal fibroblasts) distinguished by gene expression of key markers.…”