Dear Editor,
Prevalence and mortality of liver fibrosis continue to grow (Pimpin et al., 2018[17]; Weiskirchen and Tacke, 2016[24]; Leist et al., 2017[13]; Godoy et al., 2013[6]). Liver fibrosis occurs as a consequence of chronic liver damage due to various causes, such as viral infections, super-nutrition, metabolic disorders or genetic diseases (Godoy et al., 2013[6]; Ghallab et al., 2019[5]).
Recently, Winkler and colleagues performed a comprehensive study to analyze the role of miRNA in liver fibrosis and the development of hepatocellular cancer (Winkler et al., 2020[25]). For this purpose, the authors generated mice that express a constitutively active variant of serum response factor (SRF) in the liver (Winkler et al., 2020[25]). SRF regulates numerous biological processes (Olson and Nordheim 2010[16]; Ohrnberger et al., 2015[15]) and the mice develop hyperproliferative nodules that progress to HCC (Ohrnberger et al., 2015[15]). In this murine HCC model, the authors identified eight miRNA hubs and 54 target genes that regulate components of the fibrotic extracellular matrix (Winkler et al., 2020[25]). Hubs are defined as nodes in a transcriptional regulatory network with an unusual high number of connections (Anastasiadou et al., 2018[2]). Here, the miRNA families let-7, miR-30 as well as miR-29c, miR-335 and miR-338 represent central antifibrotic miRNAs (Winkler et al., 2020[25]). Importantly, these antifibrotic miRNAs (with the exception of miR-335) are regulated by the transcription factor PPARG (Winkler et al., 2020[25]). Therefore, the authors conclude that stimulating this transcription factor may represent a strategy for antifibrotic therapy.
Currently, numerous research activities are performed to identify or optimize therapies for chronic liver disease (Trauner et al., 2017[22]; Svinka et al., 2017[20]; Ghallab et al., 2016[3]; Schliess et al., 2014[18]). A particular challenge are the different etiologies with toxic (Grinberg et al., 2014[8]; 2018[7]; Albrecht et al., 2019[1]; Sezgin et al., 2018[19]), viral (Kazankov et al., 2014[12]; Theise et al., 2018[21]; Maponga et al., 2018[14]), cholestatic (Vartak et al., 2016[23]; Ghallab et al., 2019[4]; Hessel-Pras et al., 2020[9]) and genetic (Hudert et al., 2019[10]; Jansen et al., 2017[11]) mechanisms. A strength of the present study of Winkler et al.[25] is that the authors have identified hubs to target numerous antifibrotic genes simultaneously, independent of the etiology. Future studies will show, whether hub-targeting therapies will indeed ameliorate fibrosis and delay progression to HCC in mouse tumor models.