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.

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，特发性肺纤维化 （IPF） 是一种进行性、无法治愈的纤维化肺病。然而，IPF 中成纤维细胞活化的潜在机制仍然难以捉摸。在这里，我们发现 IPF 患者和博来霉素 （BLM） 诱导的肺纤维化小鼠的肺组织中 STX11 和 SNAP25 的表达水平以及活化的成纤维细胞中的表达水平下调。STX11 或 SNAP25 的上调通过促进自噬抑制 TGF-β1 诱导的人肺成纤维细胞 （HLF） 激活。然而，当使用氯喹 （CQ） 阻断自噬时，它们未能抑制成纤维细胞作用。此外，STX11 或 SNAP25 可抑制 TGF-β1 诱导的成纤维细胞增殖和迁移。在体内，STX11 的过表达在 BLM 诱导的肺纤维化小鼠中发挥其保护作用。STX11 和 SNAP25 相互促进彼此的表达。Co-IP 检测表明 STX11 与 SNAP25 有相互作用。从机制上讲，STX11-SNAP25 相互作用通过阻断 PI3K/AKT/mTOR 通路激活成纤维细胞自噬并进一步抑制成纤维细胞活化。总体而言，结果表明 STX11-SNAP25 相互作用通过阻断 PI3K/ATK/mTOR 信号通路促进成纤维细胞自噬和抑制成纤维细胞活化，从而显著抑制肺纤维化。因此，STX11 是 IPF 中一个有前途的治疗靶点。