Background: Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. Methods: Primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. Loss-of-function experiments were applied to determine the cellular functions of KDM4D in HSCs. Transcriptome analysis was applied to explore the downstream targets of KDM4D. Real-time qPCR, western blotting, immunohistochemical staining, and chromatin immunoprecipitation were performed to uncover the underlying mechanism concerning KDM4D during liver fibrogenesis. Findings: KDM4D was identified as a remarkable up-regulated histone H3 demethylase during HSC activation. The overexpression profile of KDM4D was confirmed in three fibrosis animal models and human fibrotic liver tissues. In vitro Kdm4d knockdown impaired the collagen gel contraction and migration capacity of primary HSCs. In established CCl4-induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-kappa B signaling pathways. Interpretation: KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-kappa B signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression. Fund: Shanghai New Hundred Talents Program, Shanghai Municipal Commission of Health and Family Planning, Key Developing Disciplines Program, Shanghai Key disciplines program of Health and Family Planning and Shanghai Sailing Program. (c) 2018 Published by Elsevier B.V.