Tgfb3 and Mmp13 regulated the initiation of liver fibrosis progression as dynamic network biomarkers

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.