Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Clin Transl Med. 2024 Oct;14(10):e70040. doi: 10.1002/ctm2.70040.
Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis.
CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT-PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF-β in HSCs. Notably, both global CXCL14 deletion (CXCL14) and HSC/myofibroblast-specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA-seq comparisons between CXCL14 and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo.
These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease.
肌成纤维细胞是细胞外基质的主要产生者，主要来源于肝星状细胞（HSCs），其激活在肝纤维化中起着关键作用。本研究旨在探讨趋化因子配体 14（CXCL14）在肝纤维化进展中的作用。
CXCL14 敲低显著减少了肝纤维化的程度。通过使用Ingenuity 通路分析和 qRT-PCR，鉴定出激活转录因子 3（ATF3）是 CXCL14 表达的关键上游调节因子。从机制上讲，ATF3 被证明与 CXCL14 启动子结合，促进 TGF-β 在 HSCs 中转录激活。值得注意的是，CXCL14 全局缺失（CXCL14）和 HSC/肌成纤维细胞特异性 CXCL14 敲低均显著减轻了小鼠的肝纤维化。在 CXCL14 和 WT 小鼠之间的 RNA-seq 比较中，Jak2 是下调最显著的基因，提示其在 CXCL14 抑制 HSC 失活的抗纤维化作用中的作用。此外，Jak2 过表达逆转了 CXCL14 敲低在体内引起的肝纤维化抑制。
这些发现揭示了肝纤维化中一种新的 ATF3/CXCL14/Jak2 信号轴，为该疾病提供了潜在的治疗靶点。
