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<p>Amiodarone-induced pulmonary fibrosis (AIPF) is characterized by inflammation, oxidative stress, microRNA dysregulation, fibroblast activation, and excessive extracellular matrix deposition. Norcantharidin (NCTD), a small-molecule compound with reported anti-inflammatory, antioxidant, and antifibrotic properties, has attracted attention as a potential therapeutic agent. To investigate the protective effects of NCTD against AIPF in rats. Eighteen rats were randomly divided into three groups (<i>n</i> = 6 each): a negative control group receiving vehicle, an amiodarone group, and an NCTD-treated group receiving 0.1&#xa0;mg/kg intraperitoneally for six weeks. Pulmonary fibrosis was induced by oral administration of 50&#xa0;mg/kg amiodarone for five weeks. Lung injury was assessed using hematoxylin and eosin staining and semi-quantitative scoring, collagen deposition was evaluated by Masson’s trichrome staining, and immunohistochemistry was performed for fibronectin and α-smooth muscle actin (α-SMA). Molecular and biochemical markers including tumor necrosis factor (TNF)-α, β-catenin, interleukin (IL)-1β, malondialdehyde (MDA), and glutathione (GSH) were measured, while glycogen synthase kinase (GSK)-3β was assessed by Western blot, and miRNA-30a by quantitative PCR. Amiodarone significantly increased lung injury scores, collagen deposition, α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while reducing GSH and miRNA-30a levels. NCTD treatment markedly reversed these alterations, restoring α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while increasing GSH and miRNA-30a toward normal. Histologically, NCTD preserved alveolar architecture, reduced peribronchiolar inflammation, and normalized collagen distribution. These results demonstrate that NCTD exerts potent antifibrotic, anti-inflammatory, and antioxidant effects in AIPF, likely through modulation of oxidative stress, inflammatory cytokines, microRNA expression, and the GSK-3β/β-catenin signaling pathway, highlighting its potential as a therapeutic agent for drug-induced lung injury.</p> Graphical Abstract <p></p>

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Norcantharidin attenuates amiodarone-induced pulmonary fibrosis via modulating miRNA-30a/GSK-3β/β-catenin and oxidative–inflammatory pathways

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Ahmed G. Abd Elhameed,
  • Eman H. Yousef,
  • Muhammed M. Salahuddin,
  • Mostafa M. Bahaa,
  • Amal Abdullah Alrashidi,
  • Mohamad A. El‐Gammal

摘要

Amiodarone-induced pulmonary fibrosis (AIPF) is characterized by inflammation, oxidative stress, microRNA dysregulation, fibroblast activation, and excessive extracellular matrix deposition. Norcantharidin (NCTD), a small-molecule compound with reported anti-inflammatory, antioxidant, and antifibrotic properties, has attracted attention as a potential therapeutic agent. To investigate the protective effects of NCTD against AIPF in rats. Eighteen rats were randomly divided into three groups (n = 6 each): a negative control group receiving vehicle, an amiodarone group, and an NCTD-treated group receiving 0.1 mg/kg intraperitoneally for six weeks. Pulmonary fibrosis was induced by oral administration of 50 mg/kg amiodarone for five weeks. Lung injury was assessed using hematoxylin and eosin staining and semi-quantitative scoring, collagen deposition was evaluated by Masson’s trichrome staining, and immunohistochemistry was performed for fibronectin and α-smooth muscle actin (α-SMA). Molecular and biochemical markers including tumor necrosis factor (TNF)-α, β-catenin, interleukin (IL)-1β, malondialdehyde (MDA), and glutathione (GSH) were measured, while glycogen synthase kinase (GSK)-3β was assessed by Western blot, and miRNA-30a by quantitative PCR. Amiodarone significantly increased lung injury scores, collagen deposition, α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while reducing GSH and miRNA-30a levels. NCTD treatment markedly reversed these alterations, restoring α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while increasing GSH and miRNA-30a toward normal. Histologically, NCTD preserved alveolar architecture, reduced peribronchiolar inflammation, and normalized collagen distribution. These results demonstrate that NCTD exerts potent antifibrotic, anti-inflammatory, and antioxidant effects in AIPF, likely through modulation of oxidative stress, inflammatory cytokines, microRNA expression, and the GSK-3β/β-catenin signaling pathway, highlighting its potential as a therapeutic agent for drug-induced lung injury.

Graphical Abstract