Molecular mechanisms by which Ac-SDKP regulates HSP27 via the p38MAPK/mTOR autophagy pathway to ameliorate pulmonary fibrosis

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2025-09-24 DOI:10.1016/j.cellsig.2025.112151

Wenli Li , Shuoqian Ma , Lu Liu , Yi He , Wenxin Guo , Ye Qian , Jin Wang , Liyan Zhu , Haijing Deng

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引用次数: 0

Abstract

Objectives

The main objective of this study was to investigate whether the antifibrotic tetrapeptide N-acetyl-serinyl-aspartyl-lysinyl-proline (Ac-SDKP) affects the p38MAPK/mTOR autophagy pathway by regulating heat shock protein 27 (HSP27)-mediated autophagy during the treatment of silicosis-related fibrosis to investigate the antifibrotic effect of Ac-SDKP.

Methods

In this study, we employed TGF-β1-induced human non-small cell lung cancer cells (A549), mouse embryonic fibroblasts (MEFs), and a silica-induced rat model of silicosis-related fibrosis. HSP27 interference vectors and LV-Hspb1 vectors were constructed, and the expression levels of relevant proteins were detected after lentiviral interference plasmid infection.

Results

Ac-SDKP significantly reduced the area of silicosis nodules, alpha-smooth muscle actin (α-SMA), heat shock protein 27 (HSP27), p38 mitogen-activated protein kinase (p-p38MAPK/p38MAPK), mechanistic target of rapamycin (p-mTOR/mTOR), and SQSTM1/p62; increased the ratio of light chain 3 beta II/I (LC3B-II/I); and mitigated silica-induced lung fibrosis. The p38MAPK inhibitor SB203580 further enhanced the effects of Ac-SDKP. Following lentiviral transfection to overexpress HSP27, Ac-SDKP was able to rescue the autophagy deficiency induced by HSP27 overexpression.

Conclusions

This study revealed that Ac-SDKP ameliorates pulmonary fibrosis via the p38MAPK/mTOR-dependent autophagy pathway during silicosis treatment and exerts a cytoprotective effect by enhancing autophagic flux through the inhibition of HSP27 expression. Understanding this mechanism may contribute to the development of novel therapeutic strategies for the prevention of silicosis.

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Ac-SDKP通过p38MAPK/mTOR自噬途径调控HSP27改善肺纤维化的分子机制

目的：本研究的主要目的是研究抗纤维化四肽n -乙酰丝氨酸-天冬氨酸-lysinyl-脯氨酸（Ac-SDKP）在矽肺相关纤维化治疗过程中，是否通过调节热休克蛋白27 （HSP27）介导的自噬，影响p38MAPK/mTOR自噬通路，探讨Ac-SDKP的抗纤维化作用。方法：本研究采用TGF-β1诱导的人非小细胞肺癌细胞（A549）、小鼠胚胎成纤维细胞（MEFs）和二氧化硅诱导的大鼠矽肺相关纤维化模型。构建HSP27干扰载体和LV-Hspb1载体，在慢病毒干扰质粒感染后检测相关蛋白的表达水平。结果：Ac-SDKP显著减少了硅肺结节、α-平滑肌肌动蛋白（α-SMA）、热休克蛋白27 （HSP27）、p38丝裂原活化蛋白激酶（p-p38MAPK/p38MAPK）、雷帕霉素机制靶点（p-mTOR/mTOR）、SQSTM1/p62的面积；轻链3 β II/I （LC3B-II/I）比值增加；减轻了二氧化硅引起的肺纤维化。p38MAPK抑制剂SB203580进一步增强了Ac-SDKP的作用。慢病毒转染过表达HSP27后，Ac-SDKP能够挽救HSP27过表达引起的自噬缺陷。结论：本研究揭示Ac-SDKP在矽肺治疗过程中通过p38MAPK/ mtor依赖的自噬途径改善肺纤维化，并通过抑制HSP27的表达增强自噬通量发挥细胞保护作用。了解这一机制可能有助于开发新的预防矽肺的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.