Wasson Christopher W, Perez Barreiro Esther, Del Galdo Francesco, Riobo-Del Galdo Natalia A
Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Cells. 2025 Mar 14;14(6):433. doi: 10.3390/cells14060433.
Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterised by vasculopathy with progressive fibrosis of the skin and internal organs. Tissue fibrosis is driven by activated fibroblasts (myofibroblasts) with exacerbated contractile and secretory properties. We previously reported that the long non-coding RNA HOTAIR is a key driver of SSc fibroblast activation. HOTAIR interacts with the chromatin modifiers, the polycomb repressor complex (PRC2) and coREST complex, promoting expression of pro-fibrotic genes. In this study, we show that acute activation of dermal fibroblasts from healthy subjects or SSc patients with transforming growth factor-β and other fibrotic stimuli requires the activity of the lysine-specific demethylase 1 (LSD1) subunit of the co-REST complex. Unexpectedly, LSD1 catalytic activity plays a minor role in fibrotic gene expression in HOTAIR-overexpressing fibroblasts and in maintenance of the stable myofibroblast phenotype of SSc fibroblasts. However, silencing of LSD1 in SSc fibroblasts has a profound effect on pro-fibrotic gene expression, supporting a non-canonical scaffolding function. Our study shows for the first time an essential non-canonical role for LSD1 in pro-fibrotic gene expression in SSc; however, given that this function is insensitive to LSD1 inhibitors, the therapeutic opportunities will depend on future identification of a targetable mediator.
系统性硬化症（SSc）是一种病因不明的自身免疫性疾病，其特征为血管病变，并伴有皮肤和内脏器官的进行性纤维化。组织纤维化由具有增强收缩和分泌特性的活化成纤维细胞（肌成纤维细胞）驱动。我们之前报道，长链非编码RNA HOTAIR是SSc成纤维细胞活化的关键驱动因素。HOTAIR与染色质修饰因子、多梳抑制复合物（PRC2）和coREST复合物相互作用，促进促纤维化基因的表达。在本研究中，我们发现，用转化生长因子-β和其他纤维化刺激物急性激活健康受试者或SSc患者的真皮成纤维细胞需要coREST复合物的赖氨酸特异性去甲基化酶1（LSD1）亚基的活性。出乎意料的是，LSD1催化活性在过表达HOTAIR的成纤维细胞的纤维化基因表达以及维持SSc成纤维细胞稳定的肌成纤维细胞表型中起次要作用。然而，沉默SSc成纤维细胞中的LSD1对促纤维化基因表达有深远影响，支持一种非经典的支架功能。我们的研究首次表明LSD1在SSc的促纤维化基因表达中具有重要的非经典作用；然而，鉴于该功能对LSD1抑制剂不敏感，治疗机会将取决于未来可靶向介质的鉴定。
