Histone methyltransferase SMYD2 regulates the activation of hepatic stellate cells by activating TLR4 signaling.

Liver fibrosis represents a pathological outcome in the progression of chronic liver diseases, primarily driven by the activation of hepatic stellate cells (HSCs) induced by various chronic liver injury factors. Substantial evidence indicates that under inflammatory conditions, aberrant activation of HSCs leads to excessive deposition of extracellular matrix (ECM). Therefore, identifying novel molecular targets to inhibit HSCs activation and proliferation is of significant clinical importance for the prevention and treatment of liver fibrosis. SMYD2 (SET and MYND domain containing 2) is a histone methyltransferase primarily responsible for catalyzing the methylation of lysine 36 on histone H3 (H3K36). However, the specific role and mechanisms of SMYD2 in the progression of liver fibrosis remain poorly understood. Thus, this study aims to systematically investigate the molecular regulatory mechanisms of SMYD2 in the development of liver fibrosis. Our findings demonstrate that both SMYD2 and its catalytic product, H3K36me2, are significantly upregulated in carbon tetrachloride (CCl(4))-induced liver fibrosis tissues in mice and during the spontaneous activation of primary mouse HSCs in vitro. Knockdown of SMYD2 expression significantly reduces H3K36me2 modification levels and effectively inhibits transforming growth factor-β1 (TGF-β1)-induced HSC activation. Further mechanistic studies reveal that the toll-like receptor 4 (TLR4) -nuclear factor kappa-B(NF-κB) signaling pathway is involved in this regulatory process, where Smyd2 positively regulates Tlr4 gene expression by modulating H3K36me2 modification levels. These findings suggest that SMYD2 may serve as a potential therapeutic target for liver fibrosis, warranting further exploration in subsequent clinical translational research.