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<p>Pulmonary fibrosis is a severe, chronic, and often lethal interstitial lung disease characterized by a destructive cycle of alveolar injury and inflammation, culminating in irreversible lung scarring. Its complex and multifactorial pathogenesis contributes to a poor prognosis and susceptibility to recurrent lung damage. This study employed an integrated network pharmacology and molecular docking approach to investigate the therapeutic repurposing of cilostazol for pulmonary fibrosis. Cilostazol was selected as a highly promising candidate owing to its broad pharmacological profile, encompassing anti-inflammatory, antioxidant, antiapoptotic, and antifibrotic properties. Network pharmacology analysis identified 10 potential targets of cilostazol, of which eight emerged as key network regulators: phosphodiesterase 3 (PDE3), PIK3CA, PTK2, RPS6KB1, VEGFR, F2-thrombin, ULK3 kinase, and PI3K delta. Molecular docking demonstrated that cilostazol binds to these profibrotic and fibrotic target proteins with binding affinities comparable to those of established experimental inhibitors. Experimental validation was performed using a bleomycin (BLM)-induced rat model of pulmonary fibrosis, incorporating histopathological and biochemical analyses of lung tissue and bronchoalveolar lavage fluid. Cilostazol exhibited significant antioxidant activity by reducing lipid peroxidation and restoring antioxidant enzyme levels. It exerted anti-inflammatory effects by downregulating proinflammatory cytokines (TNF-α, NO, and IL-6) and inflammatory markers (CRP, LDH, and MPO). Furthermore, cilostazol attenuated key indicators of fibrosis progression, including KL-6 and endothelin-1, alongside fibrotic markers such as TGF-β, α-SMA, and collagen I and III. At the molecular level, it significantly reduced the mRNA expression of fibrosis-associated genes, including TGF-β, fibronectin, α-SMA, collagen I, and MMP-7. Collectively, these findings demonstrate that cilostazol confers significant protection against bleomycin-induced pulmonary fibrosis through the targeted inhibition of the TGF-β/Smad, PI3K/AKT, and Wnt/β-catenin signaling cascades, highlighting its potential as a viable repurposed therapeutic strategy for inflammation-driven pulmonary fibrosis.</p>

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Pharmacological repurposing of cilostazol to attenuate the progression of pulmonary fibrosis: efficacy validation via integrated network pharmacology and in vivo experimentation

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Pranaya L. Misar,
  • Kishor V. Otari,
  • Vishal V. Pande,
  • Pradyumna P. Ige

摘要

Pulmonary fibrosis is a severe, chronic, and often lethal interstitial lung disease characterized by a destructive cycle of alveolar injury and inflammation, culminating in irreversible lung scarring. Its complex and multifactorial pathogenesis contributes to a poor prognosis and susceptibility to recurrent lung damage. This study employed an integrated network pharmacology and molecular docking approach to investigate the therapeutic repurposing of cilostazol for pulmonary fibrosis. Cilostazol was selected as a highly promising candidate owing to its broad pharmacological profile, encompassing anti-inflammatory, antioxidant, antiapoptotic, and antifibrotic properties. Network pharmacology analysis identified 10 potential targets of cilostazol, of which eight emerged as key network regulators: phosphodiesterase 3 (PDE3), PIK3CA, PTK2, RPS6KB1, VEGFR, F2-thrombin, ULK3 kinase, and PI3K delta. Molecular docking demonstrated that cilostazol binds to these profibrotic and fibrotic target proteins with binding affinities comparable to those of established experimental inhibitors. Experimental validation was performed using a bleomycin (BLM)-induced rat model of pulmonary fibrosis, incorporating histopathological and biochemical analyses of lung tissue and bronchoalveolar lavage fluid. Cilostazol exhibited significant antioxidant activity by reducing lipid peroxidation and restoring antioxidant enzyme levels. It exerted anti-inflammatory effects by downregulating proinflammatory cytokines (TNF-α, NO, and IL-6) and inflammatory markers (CRP, LDH, and MPO). Furthermore, cilostazol attenuated key indicators of fibrosis progression, including KL-6 and endothelin-1, alongside fibrotic markers such as TGF-β, α-SMA, and collagen I and III. At the molecular level, it significantly reduced the mRNA expression of fibrosis-associated genes, including TGF-β, fibronectin, α-SMA, collagen I, and MMP-7. Collectively, these findings demonstrate that cilostazol confers significant protection against bleomycin-induced pulmonary fibrosis through the targeted inhibition of the TGF-β/Smad, PI3K/AKT, and Wnt/β-catenin signaling cascades, highlighting its potential as a viable repurposed therapeutic strategy for inflammation-driven pulmonary fibrosis.