The translational relevance of our findings

The translational relevance of our findings remains uncertain at this point. On the one hand, there have been reports to suggest that boosting KDM4 activity may engender beneficial effects in vivo. For instance, Li et al. have show that KDM4 interacts with β-catenin to mediate Wnt signaling in hepatocytes thereby promoting liver regeneration [18]. On the other hand, KDM4 has also implicated in the maladaptive host response in the context of hypertrophic cardiomyopathy [39] and cancer metastasis [40] in humans. Liver fibrosis, cardiac hypertrophy, and carcinogenesis are all considered aging-associated human pathologies. Therefore, global targeting of KDM4 may bring benefits in certain populations but cause unintended side effects in others.
Acknowledgements This work was supported in part by grants from the National Natural Science Foundation of China (81700554, 81800426, and 81500441), from Education Commission of Jiangsu Province (18KJB310009), from Nanjing Medical University (2017NJMU012), from the Nanjing Municipal Administration of Health and Human Services (YKK17061), and from the Fundamental Research Funds for Central Universities (021414380323).
Introduction Hepatic fibrosis is caused by various harmful stimuli, characterized by the imbalance of extracellular matrix synthesis, degradation and deposition as well as intrahepatic connective tissue hyperplasia [[1], [2], [3], [4]]. Advanced liver fibrosis eventually leads to irreversible cirrhosis and even hepatocellular carcinoma (HCC), with liver transplantation remaining the only effective treatment for decompensated cirrhosis or advanced HCC [5,6]. Therefore, a better understanding of the molecular mechanisms underlying hepatic fibrogenesis would facilitate the development of preventive and therapeutic approaches for liver fibrosis and possibly for lethal HCC. The central event during liver fibrogenesis is the activation of hepatic stellate YM-155 hydrochloride (HSCs) [7]. Quiescent HSCs are similar to adipocytes, which can store lipid and retinoid A. Once stimulated, HSCs undergo notable phenotypic transitions, becoming more proliferative and contractile, while de novo expression of α-smooth muscle actin (α-SMA) as well as secretion of copious amounts of collagens, which disrupt liver anatomy, herald loss of liver function. This process proceeds to irreversible liver pathology and correlates with augmented mortality of patients with end-stage liver diseases [8,9]. Collagen crosslinking is an essential process for fibrotic matrix stability, which contributes to fibrosis progression and limits reversibility of liver fibrosis. Hence, inhibition of HSC activation and its collagen crosslinking ability are considered to be a promising candidate for halting or even reversing advanced fibrosis. Epigenetic regulators such as DNA methyltransferases, methyl-DNA binding proteins, histone modifying enzymes and deregulated non-coding RNA have been identified as potential points of therapeutic intervention, which has garnered wide attention [[10], [11], [12]]. Specifically, histone methylation, a reversible process, is one of the most prominent histone posttranslational modifications in response to environmental cues. Accumulating evidence suggests that the methylation of histone lysine residues is a highly dynamic modification owing to the interplay between the epigenetic “writer” lysine methyltransferases (KMTs) and “eraser” lysine demethylases (KDMs) [[13], [14], [15]]. Several KMTs have been reported to be involved in the fibrogenic phenotype of HSC-derived myofibroblasts. For instance, ASH1 orchestrates the coordinated activation of pro-fibrogenic genes including Acta2, Col1A1, and Timp-1 [16]. EZH2 contributes to the transcriptional inhibition of the nuclear receptor PPARγ, which further reprograms the adipogenic HSC towards the myofibroblast phenotype [17,18]. However, the expression patterns and potential regulatory roles of KMTs and KDMs in liver fibrosis require further exploration.