Rho-kinase inhibition reduces subretinal fibrosis.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-10-06 DOI:10.1038/s41420-025-02709-0

Yuebing Li, Tural Yarahmadov, Laura Jahnke, Tess Brodie, Sophia C Morandi, Deborah Stroka, Ali Hafezi-Moghadam, Martin S Zinkernagel, Volker Enzmann, Souska Zandi

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Abstract

Subretinal fibrosis, a consequence of choroidal neovascularization (CNV) in age-related macular degeneration (AMD), leads to irreversible vision loss due to excessive accumulation of extracellular matrix (ECM) proteins and fibrotic scarring. Anti-VEGF therapy can reverse neovascularization, but its effect on fibrosis is relatively limited. To reduce the visual impact of the fibrosis that remains after CNV. Our study investigated the use of ROCK inhibitors, fasudil and belumosudil, to treat subretinal fibrosis after CNV. The results confirmed that levels of key fibrotic markers (TGF-β1, fibronectin, vimentin, α-SMA and pMYPT1) were lower after treatment. IMC provided detailed spatial mapping of protein expression, revealing significant changes in structure and cellular composition before and after the treatment. We found that fasudil and belumosudil are effective in attenuating subretinal fibrosis by modulating the ROCK-signaling pathway, reducing ECM remodeling and attenuating the expression of markers associated with fibrosis. We hope to provide a basis for maximizing clinical benefit, focusing on optimizing dose and timing of treatment, exploring combination therapies for future anti-subretinal fibrosis research.

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rho激酶抑制可减少视网膜下纤维化。

视网膜下纤维化是年龄相关性黄斑变性（AMD）中脉络膜新生血管（CNV）的结果，由于细胞外基质（ECM）蛋白的过度积累和纤维化瘢痕导致不可逆的视力丧失。抗vegf治疗可以逆转新生血管，但其对纤维化的作用相对有限。减少CNV术后残留的纤维化对视觉的影响。我们的研究调查了使用ROCK抑制剂法舒地尔和白莫硫地尔治疗CNV后视网膜下纤维化的情况。结果证实，治疗后关键纤维化标志物TGF-β1、纤连蛋白、vimentin、α-SMA、pMYPT1水平降低。IMC提供了详细的蛋白质表达空间图谱，揭示了治疗前后结构和细胞组成的显著变化。我们发现法舒地尔和白莫硫地尔通过调节rock信号通路、减少ECM重塑和减弱与纤维化相关的标志物的表达，有效地减轻视网膜下纤维化。我们希望为今后的抗视网膜下纤维化研究提供临床获益最大化的依据，重点优化治疗剂量和时间，探索联合治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.