Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl₄-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.

中文翻译：

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14 kDa磷酸组氨酸磷酸酶是肝纤维化的潜在治疗靶标

肝纤维化是全世界发病率和死亡率的主要原因，它导致肝脏损害，严重威胁着人类健康。在我们先前的研究中，我们证明了14 kDa磷酸组氨酸磷酸酶（PHP14）在肝纤维化组织中上调，并参与了肝星状细胞（HSC）的迁移和层状脂蛋白形成。在这项研究中，我们评估了PHP14作为肝纤维化的治疗靶标，并研究了其介导肝纤维化的机制。AAV-shPhpt1管理显着减弱CCl ₄引起的小鼠肝纤维化。特别地，PHP14敲低后，与纤维化相关的炎性浸润被显着抑制。从机理上讲，PHP14通过影响巨噬细胞的足小体形成来调节巨噬细胞的募集，渗透和迁移。在肝纤维化的早期阶段，PHP14的抑制作用降低了纤维化信号的表达以及体内HSC的激活。因此，PHP14可被认为是肝纤维化的潜在治疗靶标。