Zheng Yeyi, Gong Wenjie, Wu Zhaohang, Zhang Siyi, Wang Nan, Hu Zhenyu, Shou Yanni, Xu Tianpeng, Shen Yingjie, Li Xiaokun, Jin Litai, Cong Weitao, Zhu Zhongxin
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China; Ningbo Key Laboratory of Skin Science, Ningbo College of Health Sciences, Ningbo, People's Republic of China.
Department of Pharmacy, Ningbo Women and Children's Hospital, Ningbo, People's Republic of China.
J Invest Dermatol. 2025 Apr;145(4):842-853.e8. doi: 10.1016/j.jid.2024.07.026. Epub 2024 Sep 7.
Systemic sclerosis is a typical fibrotic disease of unknown etiology that is characterized by abnormal fibroblast activation and excessive deposition of extracellular matrix. Unfortunately, effective therapeutic approaches are lacking. FGF21 plays a key role in mediating a variety of biological activities. However, its specific function in systemic sclerosis is unclear. In this study, we found that the expression of FGF21 was significantly downregulated in fibrotic skin tissue and in TGF-β-stimulated fibroblasts. Furthermore, our studies demonstrated that treatment with recombinant FGF21 in the skin significantly alleviated bleomycin-induced and TBRI-activated fibrosis and inhibited the activation of fibroblasts, whereas skin fibrosis was exacerbated by deletion of FGF21. Mechanistically, FGF21 inhibits the activity of CK2α and promotes the degradation of GLI2. In conclusion, these results indicate that FGF21 attenuates skin fibrosis through the CK2α/GLI2 signaling pathway and therefore may be a potential therapeutic target for systemic sclerosis.
系统性硬化症是一种病因不明的典型纤维化疾病，其特征是成纤维细胞异常活化和细胞外基质过度沉积。不幸的是，目前缺乏有效的治疗方法。成纤维细胞生长因子21（FGF21）在介导多种生物学活性中起关键作用。然而，其在系统性硬化症中的具体功能尚不清楚。在本研究中，我们发现FGF21在纤维化皮肤组织和转化生长因子-β（TGF-β）刺激的成纤维细胞中的表达显著下调。此外，我们的研究表明，在皮肤中用重组FGF21治疗可显著减轻博来霉素诱导的和I型转化生长因子β受体（TBRI）激活的纤维化，并抑制成纤维细胞的活化，而FGF21缺失则会加剧皮肤纤维化。从机制上讲，FGF21抑制酪蛋白激酶2α（CK2α）的活性并促进glioma相关癌基因家族锌指蛋白2（GLI2）的降解。总之，这些结果表明FGF21通过CK2α/GLI2信号通路减轻皮肤纤维化，因此可能是系统性硬化症的潜在治疗靶点。
