Inhibition of histone methyltransferase G9a aggravates phenotypic severity of hepatic lipotoxicity in non-alcoholic steatohepatitis (NASH).

Lipotoxicity is a key pathological feature in the development of non-alcoholic steatohepatitis (NASH), which is characterized by liver injury, inflammation, and fibrosis. Although lipotoxicity has been shown to induce transcriptomic alterations in liver cells, the specific role of epigenetic regulators in NASH remains elusive. In this study, we demonstrate that pharmacological inhibition of histone methyltransferase G9a significantly worsens NASH progression in mice, as evidenced by increased hepatic cell death, inflammation, and fibrosis. Additionally, at a cellular level both genetic and pharmacological inhibition of G9a in HepG2 cells increased their susceptibility to palmitic acid-induced apoptosis and sub-cellular stress. Furthermore, treatment with G9a inhibitor enhanced TGF-β induced activation of primary human hepatic stellate cells (hHSCs), implicating the role of G9a in NASH pathobiology.