Ginsenoside Re Alleviates Oxidative Stress Damage and Ferroptosis in Pulmonary Fibrosis Mice by Regulating the Nrf2/Keap1/GPX4 axis

Article Ginsenoside Re Alleviates Oxidative Stress Damage and Ferroptosis in Pulmonary Fibrosis Mice by Regulating the Nrf2/Keap1/GPX4 axis Huicai Lin 1,2,3, Zhaoqin Wen 1,2,3, Linying Feng 1,2,3, Xiaoyan Chen 4, Yongxiang Song 5, and Jiang Deng 1,2,3,* 1 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi563006, China 2 Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi563006, China 3 The Second Affiliated Hospital of Zunyi Medical University, Zunyi Medical University, Zunyi563006, China 4 Department of Pathophysiology, Zunyi Medical University, Zunyi563006, China 5 Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi563006, China * Correspondence: dengjiang1225@zmu.edu.cn; Tel.: +86-851-2864-3411; Fax: +86-851-2864-3411 Received: 30 August 2024; Revised: 28 September 2024; Accepted: 30 September 2024; Published: 17 December 2024 Abstract: Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, fibrotic interstitial lung disease with high mortality. Ginsenoside Re (G-Re) is one of the active components of ginseng, which has been proven to possess multiple pharmacological effects, including anti-inflammatory and antioxidant. Thus, G-Re is considered a potential therapeutic agent for treating PF. The present study explored the protective mechanisms of G-Re against bleomycin (BLM)-induced PF in mice and its potential as a therapeutic strategy for PF. A mouse model of BLM-induced PF was utilized to assess the effect of G-Re treatment, with N-acetylcysteine (NAC) set as a positive control agent. Various parameters such as lung function, histopathological changes, oxidative stress markers, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and its related protein expressions, including Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1), and ferroptosis signature protein glutathione peroxidase 4 (GPX4) were evaluated. Continuous administration of G-Re for 14 days significantly reduced lung injury, enhanced antioxidant capacity, activated the Nrf2/Keap1 signaling pathway, and inhibited ferroptosis as evidenced by GPX4. Additionally, G-Re treatment reduced collagen deposition, improved pulmonary function, and alleviated oxidative stress in the lung tissue of PF mice. These findings demonstrate that G-Re exerts its therapeutic effects against PF by modulating the Nrf2/Keap1/GPX4 axis and targeting oxidative stress and ferroptosis pathways, highlighting the potential of G-Re as a pharmacological intervention for PF and providing insights into the molecular mechanisms underlying its protective effects.