Xiao Yu, Huang Zhongzhou, Wang Yingyu, Wang Yan, Yu Ling, Yang Ji, Zou Hejian, Wan Weiguo, Yang Xue
Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
Central Lab, Huashan Hospital, Fudan University, Shanghai, China.
Eur J Pharmacol. 2024 Jan 15;963:176227. doi: 10.1016/j.ejphar.2023.176227. Epub 2023 Dec 8.
Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.
皮肤纤维化是系统性硬化症（SSc）最明显的临床表现，其治疗需求远未得到满足。已有研究表明，黄腐酚（Xn）对纤维化疾病具有有益作用，但其在SSc中的疗效尚未见报道。本研究旨在阐明Xn对SSc皮肤成纤维细胞（SScF）胶原合成的影响及机制。我们发现，体外培养的SScF中胶原生成增加，同时氧化应激水平失调。细胞实验表明，Xn抑制细胞增殖并促进细胞凋亡。此外，首次发现Xn可上调SScF中活性氧（ROS）和核因子红细胞2相关因子2（Nrf2）的水平，当与ROS清除剂N-乙酰半胱氨酸（NAC）联合使用时，Nrf2表达降低。重要的是，我们证明Xn通过阻断纤维化经典转化生长因子β1（TGFβ1）/Smad3信号通路显著减弱胶原合成，有趣的是，当与Nrf2抑制剂385联合使用时，该信号通路会上调。综上所述，Xn通过促进ROS诱导的氧化应激损伤和激活Nrf2来抑制TGFβ1/Smad3信号通路，从而改善胶原过度生成，提示给予Xn可能是一种治疗SSc皮肤纤维化的新策略。
