NSun2-Mediated tsRNAs Alleviate Liver Fibrosis via FAK Dephosphorylation.

IF 5.9 1区生物学 Q2 CELL BIOLOGY

Cell Proliferation Pub Date : 2025-05-12 DOI:10.1111/cpr.70058

Pengcheng Li, Sunyang Ying, Yu Zou, Xin Wang, Runxue Zhang, Cheng Huang, Moyu Dai, Kai Xu, Guihai Feng, Xin Li, Haiping Jiang, Zhikun Li, Ying Zhang, Wei Li, Qi Zhou

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引用次数: 0

Abstract

Sinusoidal capillarization - key symptoms of liver fibrosis progression - represents potential therapeutic targets. tRNA modification-mediated tRNA-derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF-1-S25 and tRF-5-V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK - crucial clinical targets. Moreover, intravenous injection of tRF-1-S25 and tRF-5-V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2-mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p-FAK pathway offers an innovative approach to treat this disease.

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nsun2介导的tsRNAs通过FAK去磷酸化减轻肝纤维化。

肝窦毛细血管化是肝纤维化进展的关键症状，是潜在的治疗靶点。tRNA修饰介导的tRNA衍生小rna （tsRNAs）在血管生成中发挥作用。NSun2是一种RNA甲基转移酶，可以产生大量的tsrna。然而，NSun2及其介导的tsRNAs在肝纤维化中的作用尚不清楚。本研究发现，NSun2缺乏可抑制窦状毛细血管形成，减轻肝纤维化。此外，NSun2敲除小鼠内皮细胞的血管生成和迁移被破坏。从机制上讲，NSun2表达的降低导致功能性tsRNAs tRF-1-S25和tRF-5-V31的改变，tRF-1-S25和tRF-5-V31通过靶向关键蛋白（包括DUSP1和FAK -关键的临床靶点）来调节窦状毛细血管化。此外，静脉注射tRF-1-S25和tRF-5-V31抑制剂可挽救小鼠肝纤维化。综上所述，由nsun2介导的trna修饰产生的tsrna抑制了正弦毛细血管化。此外，靶向DUSP1/FAK/p-FAK通路提供了一种治疗这种疾病的创新方法。

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 Proliferation 生物-细胞生物学

CiteScore

14.80

自引率

2.40%

发文量

198

审稿时长

1 months

期刊介绍： Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.