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Abstract Chronic hepatic diseases often involve fibrosis as a pivotal factor in their progression. This study investigates the regulatory mechanisms of Yin Yang 1 (YY1) in hepatic fibrosis. Our data reveal that YY1 binds to the prolyl hydroxylase domain 1 ( PHD1 ) promoter. Rats treated with carbon tetrachloride (CCl 4 ) display heightened fibrosis in liver tissues, accompanied by increased levels of YY1, PHD1, and the fibrosis marker alpha‐smooth muscle actin (α‐SMA). Elevated levels of YY1, PHD1, and α‐SMA are observed in the liver tissues of CCl 4 ‐treated rats, primary hepatic stellate cells (HSCs) isolated from fibrotic liver tissues, and transforming growth factor beta‐1 (TGF‐β1)‐induced HSCs. The human HSC cell line LX‐2, upon YY1 overexpression, exhibits enhanced TGF‐β1‐induced activation, leading to increased expression of extracellular matrix (ECM)‐related proteins and inflammatory cytokines. YY1 silencing produces the opposite effect. YY1 exerts a positive regulatory effect on the activation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway and PHD1 expression. PHD1 silencing rescues the promotion of YY1 in cell activation, ECM‐related protein expression, and inflammatory cytokine production in TGF‐β1‐treated LX‐2 cells. Overall, our findings propose a model wherein YY1 facilitates TGF‐β1‐induced HSC activation, ECM‐related protein expression, and inflammatory cytokine production by promoting PHD1 expression and activating the PI3K/AKT signaling pathway. This study positions YY1 as a promising therapeutic target for hepatic fibrosis.
Fu et al. (Wed,) studied this question.