Blockade of the calpain-1/HSP90/TGF-β1 axis by Astragaloside IV ameliorates bleomycin-induced pulmonary fibrosis
- 1Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University
- 2The First Affiliated Hospital of Jinzhou Medical University
- 3The Third Affiliated Hospital of Jinzhou Medical University
Abstract
Background: Previous studies have confirmed the therapeutic potential of Astragaloside IV (AS-IV) in pulmonary fibrosis, yet the upstream regulatory mechanisms governing TGF-β1 stability, particularly involving proteolytic enzymes, are not fully understood. This study investigates the pivotal role of calpain-1 in modulating the HSP90/TGF-β1 signaling pathway, thereby elucidating the effects of AS-IV on bleomycin (BLM)-induced pulmonary fibrosis.
Methods: Calpain-1 knockout (CAPN1 −/− ) and wild-type (WT) mice were used to establish pulmonary fibrosis models via intratracheal instillation of BLM. Both animal and cell models were administered varying doses of AS-IV for intervention. Inflammatory, oxidative stress, fibrotic, and epithelial-mesenchymal transition (EMT) markers were subsequently evaluated. Additionally, molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) experiments were employed to assess the binding interactions between AS-IV and the calpain-1/HSP90/TGF-β1 axis.
Results: The calpain-1/HSP90/TGF-β1 axis was significantly activated in BLM-induced pulmonary fibrosis mice. AS-IV ameliorated pulmonary fibrosis, EMT, oxidative stress, and inflammation while simultaneously suppressing this overactivated axis. Calpain-1 knockout inhibited HSP90 upregulation, attenuated TGF-β1/Smad2/3 activation, and reduced pulmonary fibrosis. In vivo experiments further confirmed the inhibitory effects of AS-IV and calpain-1 inhibition on lung epithelial cell injury and fibroblast proliferation. Notably, calpain-1 overexpression in MLE-12 cells abolished the protective effects of AS-IV against EMT, oxidative stress, and inflammation. Molecular docking, molecular dynamics simulations, and SPR experiments confirmed the direct binding between AS-IV and calpain-1, supporting its upstream regulatory role in this signaling axis.
Conclusion: AS-IV attenuates pulmonary fibrosis by targeting calpain-1 to disrupt the HSP90/TGF-β1 signaling axis. These findings identify calpain-1 as a novel therapeutic target and support AS-IV as a promising candidate for PF treatment.
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BibTeX
@article{wei2026blockade,
title = {{Blockade of the calpain-1/HSP90/TGF-β1 axis by Astragaloside IV ameliorates bleomycin-induced pulmonary fibrosis}},
author = {Silin Wei and Yu Liu and Bailin Tang and Yang Yu and Nan Sun and Meili Lu and Lili Sun and Guijun Wang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1864914},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1864914/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Blockade of the calpain-1/HSP90/TGF-β1 axis by Astragaloside IV ameliorates bleomycin-induced pulmonary fibrosis
AU - Silin Wei
AU - Yu Liu
AU - Bailin Tang
AU - Yang Yu
AU - Nan Sun
AU - Meili Lu
AU - Lili Sun
AU - Guijun Wang
PY - 2026
DA - 2026/10/14
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1864914
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1864914/full
AB - Background: Previous studies have confirmed the therapeutic potential of Astragaloside IV (AS-IV) in pulmonary fibrosis, yet the upstream regulatory mechanisms governing TGF-β1 stability, particularly involving proteolytic enzymes, are not fully understood. This study investigates the pivotal role of calpain-1 in modulating the HSP90/TGF-β1 signaling pathway, thereby elucidating the effects of AS-IV on bleomycin (BLM)-induced pulmonary fibrosis. Methods: Calpain-1 knockout (CAPN1 −/− ) and wild-type (WT) mice were used to establish pulmonary fibrosis models via intratracheal instillation of BLM. Both animal and cell models were administered varying doses of AS-IV for intervention. Inflammatory, oxidative stress, fibrotic, and epithelial-mesenchymal transition (EMT) markers were subsequently evaluated. Additionally, molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) experiments were employed to assess the binding interactions between AS-IV and the calpain-1/HSP90/TGF-β1 axis. Results: The calpain-1/HSP90/TGF-β1 axis was significantly activated in BLM-induced pulmonary fibrosis mice. AS-IV ameliorated pulmonary fibrosis, EMT, oxidative stress, and inflammation while simultaneously suppressing this overactivated axis. Calpain-1 knockout inhibited HSP90 upregulation, attenuated TGF-β1/Smad2/3 activation, and reduced pulmonary fibrosis. In vivo experiments further confirmed the inhibitory effects of AS-IV and calpain-1 inhibition on lung epithelial cell injury and fibroblast proliferation. Notably, calpain-1 overexpression in MLE-12 cells abolished the protective effects of AS-IV against EMT, oxidative stress, and inflammation. Molecular docking, molecular dynamics simulations, and SPR experiments confirmed the direct binding between AS-IV and calpain-1, supporting its upstream regulatory role in this signaling axis. Conclusion: AS-IV attenuates pulmonary fibrosis by targeting calpain-1 to disrupt the HSP90/TGF-β1 signaling axis. These findings identify calpain-1 as a novel therapeutic target and support AS-IV as a promising candidate for PF treatment.
SN - 1663-9812
ER -