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Tanshinone IIA Attenuates Pulmonary Fibrosis via Dual Inhibition of JNK and Smad Signaling

Congying Guo1,2, Sheng Ai1,2, Jun Chen1,2

  • 1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Antioxidants (Basel, Switzerland)
|July 28, 2026
PubMed

Insights

Tanshinone IIA (Tan-IIA) reduces pulmonary fibrosis by inhibiting the JNK/c-Jun and Smad pathways, which control Nox4 expression. This dual inhibition mitigates oxidative stress and fibroblast activation, offering a new therapeutic strategy for fibrosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Pulmonary fibrosis (PF) is a debilitating disease characterized by excessive extracellular matrix deposition.
  • Transforming growth factor-beta 1 (TGF-β1) is a key mediator of fibrosis, inducing oxidative stress and fibroblast activation partly through Nox4 expression.
  • Tanshinone IIA (Tan-IIA) is a natural compound with potential anti-fibrotic properties.

Purpose of the Study:

  • To elucidate the mechanism of TGF-β1-induced Nox4 expression in pulmonary fibrosis.
  • To investigate the anti-fibrotic effects of Tanshinone IIA (Tan-IIA).
  • To determine the therapeutic potential of targeting the JNK/c-Jun and Smad pathways in PF.

Main Methods:

  • Utilized a bleomycin-induced pulmonary fibrosis mouse model and TGF-β1-stimulated primary fibroblasts.
  • Employed pharmacological inhibitors to dissect signaling pathways (JNK/c-Jun, Smad2/3).
  • Conducted reporter assays and CUT&RUN experiments to analyze transcriptional regulation at the Nox4 promoter.

Main Results:

  • TGF-β1 induces Nox4 expression and fibrotic markers (Collagen I/III, α-SMA) via cooperative activation of JNK/c-Jun and Smad3 pathways.
  • Tan-IIA attenuates fibrosis, oxidative stress, and fibroblast activation by simultaneously inhibiting JNK/c-Jun and Smad2/3 phosphorylation and nuclear translocation.
  • A tandem c-Jun/Smad binding element in the Nox4 promoter is essential for TGF-β1-induced transcription, and Tan-IIA disrupts c-Jun and Smad2/3 binding.

Conclusions:

  • The Nox4 promoter contains a critical c-Jun/Smad binding element that integrates JNK and Smad signaling to drive profibrotic responses.
  • Tan-IIA demonstrates a novel therapeutic strategy for pulmonary fibrosis by concurrently targeting the JNK/c-Jun and Smad pathways.
  • Tan-IIA effectively suppresses Nox4-dependent oxidative stress and fibroblast activation, offering promise for treating fibrotic diseases.
Keywords:
JNK and Smad signalingNADPH oxidase 4fibroblast activationpulmonary fibrosistanshinone IIA

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