Zhang Xiaoye, Sun Jinjian, Guo Jia, Hu Xiaoru, Zhou Junyu, Xie Xiaoyun, Chen Xiang, Luo Hui, Liu Hong, Tian Yuzi
Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hunan Engineering Research Center of Skin Health and Disease, Central South University, Changsha, Hunan, China.
Cell Commun Signal. 2025 Apr 29;23(1):206. doi: 10.1186/s12964-025-02210-2.
Skin fibrosis presents a major challenge for clinicians treating conditions like systemic sclerosis (SSc) due to its progressive course and limited treatment options. While the role of metabolism in fibrosis has gained increasing attention, the crucial alterations of metabolic pathway and the underlying signaling of metabolic interconnections in regulating SSc-related skin fibrosis remain largely elusive.
Metabolomic analysis was performed on plasma samples from 35 SSc patients to identify metabolic alterations. In bleomycin (BLM)- and hypochlorous acid (HOCL)-induced skin fibrosis mouse models, we assessed the impact of global A2a receptor knockout on skin fibrosis. Single-cell RNA sequencing of mouse skin was utilized to investigate the role of A2A in fibroblasts during fibrotic challenge. Human dermal fibroblasts were used in in vitro experiments, employing RNA sequencing and Seahorse assays, to assess the relationship between A2A signaling and fatty acid oxidation (FAO). Finally, fibroblast-specific conditional A2a knockout mice were used to test the effects of specifically targeting A2A in dermal fibroblasts.
Adenosine-centered nucleotide metabolism was elevated in the plasma of SSc patients. Mechanistically, by stimulating dermal fibroblasts with key pathogenic cytokines associated with SSc, we observed significant changes in adenosine receptor A2A expression in response to IL-1β. Immunofluorescence revealed upregulation of A2A expression in dermal fibroblasts of SSc patients. Further, global A2a knockout significantly attenuated skin fibrosis in both BLM- and HOCL-induced skin fibrosis mouse models. Single-cell RNA sequencing of mouse skin revealed significant alterations in fatty acid metabolism in fibroblasts from A2a-deficient mice following fibrotic challenge. RNA sequencing, Seahorse assays and in vitro experiments showed that A2A inhibition promotes FAO by upregulating CPT1A expression via suppressing CREB phosphorylation, alleviating fibrosis in human primary dermal fibroblasts. Furthermore, targeted intervention of A2a specifically in fibroblasts improves outcomes and increases CPT1A expression in BLM-induced skin fibrosis mouse model.
Our study highlights the crucial interplay between adenosine metabolism-A2A receptor axis and FAO in SSc-associated skin fibrosis, suggesting that targeting the adenosine receptor A2A-FAO metabolic axis offers a promising therapeutic strategy for skin fibrosis.
皮肤纤维化因其进展性病程和有限的治疗选择，给治疗系统性硬化症（SSc）等疾病的临床医生带来了重大挑战。虽然代谢在纤维化中的作用日益受到关注，但代谢途径的关键改变以及代谢相互连接在调节SSc相关皮肤纤维化中的潜在信号传导仍在很大程度上尚不明确。
对35例SSc患者的血浆样本进行代谢组学分析，以确定代谢改变。在博来霉素（BLM）和次氯酸（HOCL）诱导的皮肤纤维化小鼠模型中，我们评估了全局A2a受体敲除对皮肤纤维化的影响。利用小鼠皮肤的单细胞RNA测序来研究A2A在纤维化刺激过程中在成纤维细胞中的作用。在体外实验中使用人皮肤成纤维细胞，采用RNA测序和海马分析，以评估A2A信号传导与脂肪酸氧化（FAO）之间的关系。最后，使用成纤维细胞特异性条件性A2a敲除小鼠来测试特异性靶向真皮成纤维细胞中A2A的效果。
SSc患者血浆中以腺苷为中心的核苷酸代谢升高。机制上，通过用与SSc相关的关键致病细胞因子刺激真皮成纤维细胞，我们观察到腺苷受体A2A表达因白细胞介素-1β而发生显著变化。免疫荧光显示SSc患者真皮成纤维细胞中A2A表达上调。此外，全局A2a敲除在BLM和HOCL诱导的皮肤纤维化小鼠模型中均显著减轻了皮肤纤维化。小鼠皮肤的单细胞RNA测序显示，在纤维化刺激后，A2a缺陷小鼠的成纤维细胞中脂肪酸代谢发生了显著改变。RNA测序、海马分析和体外实验表明，A2A抑制通过抑制CREB磷酸化上调CPT1A表达来促进FAO，从而减轻人原代真皮成纤维细胞中的纤维化。此外，在BLM诱导的皮肤纤维化小鼠模型中，特异性地在成纤维细胞中对A2a进行靶向干预可改善结果并增加CPT1A表达。
我们的研究突出了腺苷代谢 - A2A受体轴与FAO在SSc相关皮肤纤维化中的关键相互作用，表明靶向腺苷受体A2A - FAO代谢轴为皮肤纤维化提供了一种有前景的治疗策略。
