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Purpose <p>Pulmonary fibrosis is a clinically significant complication associated with radiation exposure. <i>Mangifera indica</i> L. (MI) peels and seeds (Fam. Anacardiaceae) contain abundant bioactive components with efficient antifibrotic activities. In this study, a network pharmacology database has been used to identify the underlying mechanisms and validate the long-term impact of MI kernel seed extract (MIE) against radiation-induced pulmonary fibrosis.</p> Methods <p>MIE was first analyzed by the LC-ESI-TOF–MS/MS, and 28 active constituents were identified based on relative peak intensity. Network pharmacology analysis identified the PDGF, PI3K, AKT, GSK-3β and MMP-2 enriched signaling pathways of MIE metabolites against lung fibrosis incidence. Thereafter, following validation of MIE safety through acute and subacute toxicity studies, the in-vivo antifibrotic assessment of MIE in thoracic irradiated rats was conducted. Molecular docking studies were performed to characterize the binding affinities and interaction profiles of major MIE metabolites (gluconic acid, gallic acid, and mangiferin) with key fibrosis-related targets (PDGF and MMP-2).</p> Results <p>Histopathological analysis, collagen deposition on Masson's tri-chrome staining, and immunohistochemical expression of TGF-β1 and fibronectin proteins revealed an early lung fibrosis after six weeks from acute γ-radiation exposure; MIE treatment mitigated these changes and decreased the expression of pro-fibrotic markers. The computational prediction effect of MIE on fibrotic signaling pathway, was established experimentally by suppression of PDGF, PI3K, GSK-3β and MMP-2 lung levels by 14%, 45%, 35% and 14%, respectively, supporting the modulatory effect of MIE on signaling pathway implicated in fibrogenesis. Moreover, the energetically favorable interactions between MIE metabolites, and PDGF and MMP-2 in docking analysis suggest the potential contribution of the identified metabolites to the pharmacological activity and aligned with their in vivo activity.</p> Conclusions <p>MIE could be a safe and promising long-term protective herbal extract capable of delaying early pulmonary fibrosis induced by radiation through modulation of MMP-2 and PDGF/PI3K-AKT/GSK-3β-related signaling pathways.</p> Graphical Abstract <p></p>

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Computational Investigation of Mangifera indica Seed Kernel Extract Against Radiation Induced Pulmonary Fibrosis: In vivo PDGF/PI3K-AKT/GSK3β Pathway

  • 期刊论文

  • 发表日期：

    2026年6月25日

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  • Fatma A. Mokhtar,
  • Nahla S. El-Gazzar,
  • Sebaey Mahgoub,
  • Noha A. Fadel,
  • Rania M. El-Hazek,
  • Walaa A. El-Sabbagh

摘要

Purpose

Pulmonary fibrosis is a clinically significant complication associated with radiation exposure. Mangifera indica L. (MI) peels and seeds (Fam. Anacardiaceae) contain abundant bioactive components with efficient antifibrotic activities. In this study, a network pharmacology database has been used to identify the underlying mechanisms and validate the long-term impact of MI kernel seed extract (MIE) against radiation-induced pulmonary fibrosis.

Methods

MIE was first analyzed by the LC-ESI-TOF–MS/MS, and 28 active constituents were identified based on relative peak intensity. Network pharmacology analysis identified the PDGF, PI3K, AKT, GSK-3β and MMP-2 enriched signaling pathways of MIE metabolites against lung fibrosis incidence. Thereafter, following validation of MIE safety through acute and subacute toxicity studies, the in-vivo antifibrotic assessment of MIE in thoracic irradiated rats was conducted. Molecular docking studies were performed to characterize the binding affinities and interaction profiles of major MIE metabolites (gluconic acid, gallic acid, and mangiferin) with key fibrosis-related targets (PDGF and MMP-2).

Results

Histopathological analysis, collagen deposition on Masson's tri-chrome staining, and immunohistochemical expression of TGF-β1 and fibronectin proteins revealed an early lung fibrosis after six weeks from acute γ-radiation exposure; MIE treatment mitigated these changes and decreased the expression of pro-fibrotic markers. The computational prediction effect of MIE on fibrotic signaling pathway, was established experimentally by suppression of PDGF, PI3K, GSK-3β and MMP-2 lung levels by 14%, 45%, 35% and 14%, respectively, supporting the modulatory effect of MIE on signaling pathway implicated in fibrogenesis. Moreover, the energetically favorable interactions between MIE metabolites, and PDGF and MMP-2 in docking analysis suggest the potential contribution of the identified metabolites to the pharmacological activity and aligned with their in vivo activity.

Conclusions

MIE could be a safe and promising long-term protective herbal extract capable of delaying early pulmonary fibrosis induced by radiation through modulation of MMP-2 and PDGF/PI3K-AKT/GSK-3β-related signaling pathways.

Graphical Abstract