Pharmacological targeting of ferroptosis in hypoxia-induced pulmonary edema: therapeutic potential of ginsenoside Rg3 through activation of the PI3K/AKT pathway
BackgroundHigh-altitude pulmonary edema (HAPE), a severe manifestation of hypoxia-induced pulmonary hypertension, continues to present a major health concern in high-altitude environments due to the absence of efficient preventive measures. This investigation explores the protective influence of gin...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1644436/full |
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| Summary: | BackgroundHigh-altitude pulmonary edema (HAPE), a severe manifestation of hypoxia-induced pulmonary hypertension, continues to present a major health concern in high-altitude environments due to the absence of efficient preventive measures. This investigation explores the protective influence of ginsenoside Rg3 (G-Rg3), an active substance derived from the botanical drug Panax ginseng C.A.Mey., on the prevention of HAPE progression.MethodsA mouse model mimicking exposure to 6000-m altitude (n = 63 C57BL/6 mice) was employed to evaluate the impact of G-Rg3 (15/30 mg/kg) using histopathological, biochemical, and multi-dimensional molecular assessments. Western blotting, network pharmacology and computational simulations were utilized to identify molecular targets of G-Rg3. The role of the PI3K/AKT signaling pathway was further validated through experiments using the PI3K/AKT inhibitor LY294002.ResultsPre-treatment with G-Rg3 effectively alleviated HAPE, maintained the stability of lung ultrastructure, and inhibited inflammatory mediators and oxidative stress indicators. Mechanistically, G-Rg3 prevented ferroptosis by stimulating the PI3K/AKT signaling pathway, as evidenced by the upregulation of protective proteins (GPX4, Nrf2, HO-1, SLC7A11, FTH1, FLC) and the downregulation of iron metabolism regulatory factors (TFRC, COX2). Network pharmacology and molecular docking analysis confirmed that PI3K/AKT is the core target of G-Rg3, and the protective effect disappeared when this pathway was inhibited. G-Rg3 uniquely regulated oxidative stress and inflammation by inhibiting ferroptosis, demonstrating adaptability to high-altitude environments.ConclusionThis research examined the pharmacological impacts and molecular pathways of ginseng active monomers on HAPE, suggesting the potential of G-Rg3 as a promising treatment option for this condition. |
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| ISSN: | 1663-9812 |