Overexpression of STX11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the PI3K/AKT/mTOR pathway

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-11-11 DOI:10.1038/s41392-024-02011-y
Guichuan Huang, Xiangsheng Yang, Qingyang Yu, Qun Luo, Chunrong Ju, Bangyan Zhang, Yijing Chen, Zihan Liang, Shu Xia, Xiaohua Wang, Dong Xiang, Nanshan Zhong, Xiao Xiao Tang
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Abstract

Fibroblast activation plays an important role in the occurrence and development of idiopathic pulmonary fibrosis (IPF), which is a progressive, incurable, and fibrotic lung disease. However, the underlying mechanism of fibroblast activation in IPF remains elusive. Here, we showed that the expression levels of STX11 and SNAP25 were downregulated in the lung tissues from patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis as well as in the activated fibroblasts. Upregulation of STX11 or SNAP25 suppressed TGF-β1-induced activation of human lung fibroblasts (HLFs) via promoting autophagy. However, they failed to suppress fibroblast actviation when autophagy was blocked with the use of chloroquine (CQ). In addition, STX11 or SNAP25 could inhibit TGF-β1-induced fibroblast proliferation and migration. In vivo, overexpression of STX11 exerted its protective role in the mice with BLM-induced lung fibrosis. STX11 and SNAP25 mutually promoted expression of each other. Co-IP assay indicated that STX11 has an interaction with SNAP25. Mechanistically, STX11-SNAP25 interaction activated fibroblast autophagy and further inhibited fibroblast activation via blocking the PI3K/AKT/mTOR pathway. Overall, the results suggested that STX11-SNAP25 interaction significantly inhibited lung fibrosis by promoting fibroblast autophagy and suppressing fibroblast activation via blocking the PI3K/ATK/mTOR signaling pathway. Therefore, STX11 serves as a promising therapeutic target in IPF.

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过表达 STX11 可通过 PI3K/AKT/mTOR 通路抑制成纤维细胞的活化,从而减轻肺纤维化程度
成纤维细胞活化在特发性肺纤维化(IPF)的发生和发展中起着重要作用。然而,IPF 中成纤维细胞活化的内在机制仍然难以捉摸。在这里,我们发现在 IPF 患者和博莱霉素(BLM)诱导的肺纤维化小鼠的肺组织中,以及在活化的成纤维细胞中,STX11 和 SNAP25 的表达水平下调。通过促进自噬,上调 STX11 或 SNAP25 可抑制 TGF-β1 诱导的人肺成纤维细胞(HLFs)的活化。然而,当使用氯喹(CQ)阻断自噬作用时,它们未能抑制成纤维细胞的活化。此外,STX11 或 SNAP25 还能抑制 TGF-β1 诱导的成纤维细胞增殖和迁移。在体内,STX11的过表达对BLM诱导的肺纤维化小鼠具有保护作用。STX11 和 SNAP25 的表达相互促进。Co-IP 分析表明,STX11 与 SNAP25 存在相互作用。从机理上讲,STX11-SNAP25相互作用激活了成纤维细胞的自噬,并通过阻断PI3K/AKT/mTOR通路进一步抑制了成纤维细胞的活化。总之,研究结果表明,STX11-SNAP25相互作用通过促进成纤维细胞自噬,并通过阻断PI3K/ATK/mTOR信号通路抑制成纤维细胞活化,从而显著抑制肺纤维化。因此,STX11有望成为治疗IPF的靶点。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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