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One of the hallmark events during liver fibrosis is the transition of quiescent hepatic stellate cells (HSC) into activated myofibroblasts, which are responsible for the production and deposition of pro-fibrogenic proteins. The epigenetic mechanism underlying HSC trans-differentiation is not fully understood. In the present study we investigated the contribution of histone H3K9 demethylase KDM4 in this process. We report that expression levels of KDM4 were down-regulated during HSC activation paralleling the up-regulation of alpha smooth muscle cell actin (Acta2), a marker of mature myofibroblast. Furthermore, HSCs isolated from mice induced to develop liver fibrosis exhibit lowered KDM4 expression compared to the control mice. In accordance, KDM4 depletion with siRNA accelerated HSC activation. Of interest, the loss of KDM4 was mirrored by the repression of miR-29, an antagonist of liver fibrosis, during HSC activation both in vitro and in vivo. KDM4 knockdown resulted in the down-regulation of miR-29 expression. Mechanistically, the sequence-specific transcription factor SREBP2 interacted with KDM4 to activate miR-29 transcription. In conclusion, our data delineate a novel epigenetic mechanism underlying HSC activation. Targeting this axis may yield potential therapeutics against liver fibrosis. • KDM4 levels are down-regulated in activated HSCs both in vitro and in vivo. • KDM4 suppresses HSC activation. • SREBP2 is down-regulated in activated HSCs and suppresses HSC activation. • KDM4 interacts with SREBP2 to activate miR-29 transcription. [ABSTRACT FROM AUTHOR]