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Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway
Yu Xiao1, Zhongzhou Huang1, Yingyu Wang1
1Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
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.
Insights
Xanthohumol (Xn) may treat systemic sclerosis (SSc) skin fibrosis by reducing collagen. It works by increasing oxidative stress and activating Nrf2, which suppresses the fibrotic TGFβ1/Smad3 pathway.
Area of Science:
- Biochemistry
- Dermatology
- Pharmacology
Background:
- Systemic sclerosis (SSc) causes skin fibrosis, a condition with limited treatment options.
- Xanthohumol (Xn), known for anti-fibrotic properties, has not been studied for SSc.
- Investigating Xn's effects on SSc skin fibroblasts (SScF) is crucial.
Purpose of the Study:
- To determine the efficacy and mechanism of Xanthohumol (Xn) on collagen synthesis in SSc skin fibroblasts (SScF).
- To explore Xn's impact on oxidative stress and key fibrotic pathways in SScF.
Main Methods:
- Cultured SScF to assess collagen production and oxidative stress.
- Treated SScF with Xn to evaluate effects on proliferation, apoptosis, reactive oxygen species (ROS), and Nrf2 levels.
- Investigated the interaction between Xn, ROS, Nrf2, and the TGFβ1/Smad3 pathway using inhibitors and scavengers.
Main Results:
- SScF exhibited increased collagen production and altered oxidative stress levels in vitro.
- Xn inhibited SScF proliferation, promoted apoptosis, and upregulated ROS and Nrf2.
- Xn attenuated collagen synthesis by inhibiting the TGFβ1/Smad3 pathway, an effect modulated by ROS and Nrf2.
Conclusions:
- Xanthohumol (Xn) suppresses collagen overproduction in SSc skin fibrosis.
- Xn acts by promoting ROS-induced oxidative stress and activating Nrf2, leading to TGFβ1/Smad3 pathway inhibition.
- Xn shows potential as a novel therapeutic agent for SSc-related skin fibrosis.
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