Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated ( ENHO ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin 34–76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19 , an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin 34–76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin 34–76 -induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.

中文翻译：

---

阿德洛平在系统性硬化症中减弱成纤维细胞活化和纤维化

纤维化疾病给现代社会带来了重大的社会经济挑战，并且治疗选择有限。 Adropin，一种由能量稳态相关编码的肽激素（恩霍) 基因与新陈代谢和血管稳态有关，但其在纤维化发病机制中的作用仍然是个谜。在这里，我们使用机器学习方法与功能性体外和体内实验相结合，将 adropin 描述为参与系统性硬化症 (SSc) 成纤维细胞活化和组织纤维化的潜在调节剂。我们证明了 adropin/ 的持续下调恩霍多个 SSc 患者队列的皮肤中。典型的促纤维化细胞因子 TGFβ 减少了 adropin/恩霍以 JNK 依赖性方式表达。通过生物活性 adropin 的治疗应用恢复 adropin 信号传导34–76肽反过来抑制原代人真皮成纤维细胞、三维全层皮肤等效物、博来霉素诱导的肺纤维化和硬皮病慢性移植物抗宿主病（sclGvHD）的小鼠模型中TGFβ诱导的成纤维细胞活化和纤维化组织重塑，和精密切割的人体皮肤切片。击倒探地雷达19，一种adropin受体，消除了adropin在成纤维细胞中的抗纤维化作用。 RNA-seq 证明 adropin 的抗纤维化作用34–76在功能上与 GLI1 依赖性促纤维化转录网络的失活相关，这一点已通过培养的人真皮成纤维细胞、sclGvHD 小鼠模型和精密切割的人皮肤切片在体外、体内和离体实验中得到证实。 ChIP-seq 证实了 adropin34–76-诱导TGFβ/GLI1信号传导的变化。我们的研究表征了 TGFβ 诱导的 adropin/ 下调恩霍SSc 是一种典型的系统性纤维化疾病，可释放促纤维化 GLI1 信号传导不受控制的激活，其表达是 SSc 的潜在病理机制。