2. Academic Validation
  3. Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway

Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway

  • Eur J Pharmacol. 2023 Dec 8:176227. doi: 10.1016/j.ejphar.2023.176227.
Yu Xiao 1,  Zhongzhou Huang 1,  Yingyu Wang 1,  Yan Wang 2,  Ling Yu 3,  Ji Yang 4,  Hejian Zou 1,  Weiguo Wan 5,  Xue Yang 6
Affiliations

Affiliations

  • 1 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
  • 2 Central Lab, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China.
  • 4 Division of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 6 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 38072040 DOI: 10.1016/j.ejphar.2023.176227
Abstract

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.

Keywords

Fibrosis; Oxidative stress; Systemic sclerosis; Xanthohumol.

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