塞来昔布通过减弱YAP/TAZ信号通路抑制脂肪祖细胞-肌成纤维细胞转分化，从而抑制皮肤纤维化

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-14 DOI:10.1016/j.lfs.2025.123914

Masaki Arioka , Hiroaki Matsunaga , Shin Ishikane , Kazuma Ito , Kohei Hashimoto , Yi Wang , Kazunobu Igawa , Fumi Takahashi-Yanaga

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引用次数: 0

摘要

背景和目的过度纤维化和异常瘢痕形成，如增生性瘢痕和瘢痕疙瘩，对伤口愈合提出了重大挑战。来源于多种细胞类型的肌成纤维细胞，包括脂肪细胞祖细胞，在驱动纤维化组织形成中起着至关重要的作用。本研究旨在探讨选择性环氧化酶-2抑制剂塞来昔布的抗纤维化潜能，并阐明其潜在机制。我们利用博来霉素诱导的硬化症小鼠模型来评估局部给药塞来昔布对皮肤纤维化的体内影响。采用3T3-L1脂肪祖细胞系进行体外实验，研究塞来昔布对转化生长因子-β (TGF-β1)诱导的肌成纤维细胞转分化的影响，以及ye相关蛋白(YAP)/转录共激活因子与pdz结合基序（TAZ）信号通路的参与。关键结果：在博来霉素诱导的纤维化模型中，局部塞来昔布治疗可显著减轻真皮增厚并保留皮内脂肪组织。在体外，塞来昔布抑制TGF-β1诱导的3T3-L1细胞的肌成纤维细胞转分化，表现为α-平滑肌肌动蛋白表达减少和细胞外基质生成减少。在机制上，塞来昔布通过抑制YAP和TAZ蛋白表达并阻止其核易位来抑制TGF-β1诱导的YAP/TAZ信号通路的激活，而不影响典型的TGF-β/SMAD信号通路。结论和意义来昔布通过靶向YAP/TAZ信号通路，抑制脂肪祖细胞-肌成纤维细胞转分化，抑制细胞外基质的生成，具有抗纤维化作用。这些结果表明，塞来昔布可以作为一种有前景的治疗异常瘢痕和纤维化的药物，为伤口愈合的新型抗纤维化策略提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Celecoxib inhibits skin fibrosis via suppressing adipocyte progenitor–myofibroblast transdifferentiation by attenuating the YAP/TAZ signaling pathway

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Celecoxib inhibits skin fibrosis via suppressing adipocyte progenitor–myofibroblast transdifferentiation by attenuating the YAP/TAZ signaling pathway

Background and purpose

Excessive fibrosis and abnormal scarring, such as hypertrophic scars and keloids, pose significant challenges in wound healing. Myofibroblasts derived from various cell types, including adipocyte progenitors, play a crucial role in driving fibrotic tissue formation. This study aimed to investigate the anti-fibrotic potential of celecoxib, a selective cyclooxygenase-2 inhibitor, and elucidate its underlying mechanisms.

Experimental approach

We utilized a bleomycin-induced sclerosis mouse model to evaluate the in vivo effects of topically administered celecoxib on skin fibrosis. In vitro experiments were conducted using the 3T3-L1 adipocyte progenitor cell line to investigate the impact of celecoxib on transforming growth factor-β (TGF-β1)-induced myofibroblast transdifferentiation and the involvement of the Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway.

Key results

Topical celecoxib treatment significantly attenuated dermal thickening and preserved the intradermal adipose tissue in the bleomycin-induced fibrosis model. In vitro, celecoxib suppressed TGF-β1-induced myofibroblast transdifferentiation in 3T3-L1 cells, as evidenced by reduced α-smooth muscle actin expression and extracellular matrix production. Mechanistically, celecoxib inhibited the TGF-β1-induced activation of the YAP/TAZ signaling pathway by suppressing YAP and TAZ protein expressions and preventing their nuclear translocation, without affecting the canonical TGF-β/SMAD signaling pathway.

Conclusion and implications

Celecoxib exhibited anti-fibrotic effects by targeting the YAP/TAZ signaling pathway, inhibiting adipocyte progenitor–myofibroblast transdifferentiation, and suppressing extracellular matrix production. These results suggest that celecoxib could serve as a promising therapeutic agent for abnormal scarring and fibrosis, offering valuable insights into novel anti-fibrotic strategies for wound healing.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.