肝纤维化是一种慢性肝病，其中肝星状细胞（HSC）的激活引起细胞外基质成分的大量增加。HOXC8已被证明参与调节肿瘤细胞的增殖和纤维化，但HOXC8在肝纤维化中的作用和潜在的分子机制尚未得到研究。在本研究中，我们发现，在CCl4诱导的肝纤维化小鼠模型和TGF-β处理的人类（LX-2）HSC细胞中，HOXC8 mRNA和蛋白质升高。重要的是，我们观察到下调HOXC8可缓解肝纤维化，并在体内抑制CCl4诱导的纤维化基因诱导。此外，抑制HOXC8可以抑制TGF-β1诱导的LX-2细胞的HSC激活和纤维化相关基因（α-SMA和COL1a1）的表达，而HOXC8的过表达则具有相反的效果。从机制上，我们证明了HOXC8可以激活TGF-β1转录，并增强磷酸化Smad2/Smad3水平，表明HOXC8和TGF-β1之间存在正反馈环路，促进TGF-β信号和随后的HSC激活。综上所述，我们的数据强烈表明，HOXC8/TGF-β1正反馈环路在控制HSC激活和肝纤维化过程中发挥重要作用，提示抑制HOXC8可能作为促进治疗肝纤维化疾病的策略。 版权所有©2023 Elsevier Inc.。

Liver fibrosis occurs in any chronic liver disease, where extraordinary increase of extracellular matrix components is caused by the hepatic stellate cell (HSC) activation. HOXC8 has been disclosed to participate inregulating cell proliferation and fibrosis in tumors. However, the role of HOXC8 in liver fibrosis and the underlying molecular mechanisms has not yet been investigated. In this study, we founded that HOXC8 mRNA and protein was elevated in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and transforming growth factor-β (TGF-β)-treated human (LX-2) HSC cells. Importantly, we observed that downregulating HOXC8 alleviates liver fibrosis and suppressed the fibrogenic gene induction induced by CCl4 in vivo. In addition, inhibition of HOXC8 suppressed the HSC activation and the expression of fibrosis-associated genes (α-SMA and COL1a1) induced by TGF-β1 in LX-2 cells in vitro, while HOXC8 overexpression had the opposite effects. Mechanistically, we demonstrated HOXC8 activates TGFβ1 transcription and enhanced the phosphorylated Smad2/Smad3 levels, suggesting a positive feedback loop between HOXC8 and TGF-β1 that facilitates TGF-β signaling and subsequent HSCs activation. Collectively, our data strongly indicated that a HOXC8/TGF-β1 positive feedback loop plays as a critical role in controlling the HSC activation and in the liver fibrosis process, suggesting that inhibition of HOXC8 may serve as a promoting therapeutic strategy for diseases characterized by liver fibrosis.Copyright © 2023 Elsevier Inc. All rights reserved.