Liver fibrogenesis is a complex scar‐forming process in the liver. We suggested that the liver first responded to chronic injuries with gradual changes, then reached the critical state and ultimately resulted in cirrhosis rapidly. This study aimed to identify the tipping point and key molecules driving liver fibrosis progression. Mice model of liver fibrosis was induced by thioacetamide (TAA), and liver tissues were collected at different time‐points post‐TAA administration. By dynamic network biomarker (DNB) analysis on the time series of liver transcriptomes, the week 9 post‐TAA treatment (pathologically relevant to bridging fibrosis) was identified as the tipping point just before the significant fibrosis transition, with 153 DNB genes as key driving factors. The DNB genes were functionally enriched in fibrosis‐associated pathways, in particular, in the top‐ranked DNB genes, Tgfb3 negatively regulated Mmp13 in the interaction path and they formed a bistable switching system from a dynamical perspective. In the in vitro study, Tgfb3 promoted fibrogenic genes and down‐regulate Mmp13 gene transcription in an immortalized mouse HSC line JS1 and a human HSC line LX‐2. The presence of a tipping point during liver fibrogenesis driven by DNB genes marks not only the initiation of significant fibrogenesis but also the repression of the scar resolution.

中文翻译：

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Tgfb3 和 Mmp13 作为动态网络生物标志物调节肝纤维化进展的开始

肝纤维化是肝脏中一个复杂的瘢痕形成过程。我们建议肝脏首先对慢性损伤做出逐渐变化的反应，然后达到临界状态并最终迅速导致肝硬化。本研究旨在确定驱动肝纤维化进展的临界点和关键分子。通过硫代乙酰胺（TAA）诱导肝纤维化小鼠模型，并在TAA给药后的不同时间点收集肝组织。通过对肝脏转录组时间序列的动态网络生物标志物 (DNB) 分析，TAA 治疗后第 9 周（病理上与桥接纤维化相关）被确定为显着纤维化转变之前的临界点，其中 153 个 DNB 基因是关键驱动因素因素。DNB 基因在纤维化相关通路中功能丰富，特别是在排名靠前的DNB基因中，Tgfb3在相互作用路径中负调控Mmp13，从动力学的角度来看，它们形成了一个双稳态切换系统。在里面在体外研究中，Tgfb3 在永生化小鼠 HSC 系 JS1 和人类 HSC 系 LX-2 中促进纤维化基因并下调 Mmp13 基因转录。在由 DNB 基因驱动的肝纤维化过程中出现一个临界点不仅标志着显着纤维化的开始，而且也标志着瘢痕消退的抑制。