Glabridin protects against paraquat-induced acute lung injury by targeting ME1 to mitigate oxidative stress, mitochondrial dysfunction, and cGAS-STING activation

  • Free Radic Biol Med. 2025 Aug 1:235:317-334. doi: 10.1016/j.freeradbiomed.2025.04.016.
Mingming Zhao  1 ,  Xuanhai Xie  2 ,  Yitian Ding  2 ,  Qiang Zhang  3 ,  Xinheng Liu  4 ,  Taotao Lin  2 ,  Linhua Lan  5 ,  Guangliang Hong  6
Affiliations
  • 1. Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China; Wenzhou Medical University, Wenzhou, 325000, China; CixiBiomedical Research Institute, Wenzhou Medical University, Ningbo, 315300, China.
  • 2. Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China; Wenzhou Medical University, Wenzhou, 325000, China.
  • 3. Emergency Department, The People's Hospital of Yuhuan, Taizhou, 317600, China.
  • 4. Wenzhou Medical University, Wenzhou, 325000, China.
  • 5. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreaic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 6. Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China; Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: [email protected].
PMID: 40316060 DOI: 10.1016/j.freeradbiomed.2025.04.016
Abstract

Background: Acute lung injury (ALI) resulting from paraquat (PQ) poisoning constitutes a significant mortality risk, predominantly due to oxidative stress and mitochondrial dysfunction. Despite this, effective treatment options are currently limited.

Purpose: This study examines the protective effects of Glabridin (Glab), a flavonoid with noted antioxidant properties, against PQ-induced ALI, with a focus on its mitochondrial function and modulation of oxidative stress.

Methods: The research utilized human normal lung epithelial line BEAS-2B cells (B2B) and PQ-exposed C57BL/6J mice to evaluate the role of Glab. Assessments included lung inflammation, oxidative stress markers, and mitochondrial dysfunction, as well as the involvement of the cGAS-STING and Caspase-3 pathways. Molecular docking and western blot analyses were used to investigate the interaction between Glab and malic enzyme 1 (ME1).

Results: The findings indicate that Glab significantly enhances survival rates, reduces inflammation, and mitigates oxidative stress in PQ-exposed mice. In vitro experiments demonstrated that Glab inhibited the cGAS-STING and Caspase-3 pathways, release of mitochondrial contents (cytochrome C and mtDNA), decreased mitochondrial ROS production, and stabilized ME1, resulting in increased NADPH levels.

Conclusion: Glab confers protection against PQ-induced ALI by modulating oxidative stress, preserving mitochondrial function, and inhibiting both inflammatory and apoptotic pathways. Notably, the stabilization of malic enzyme 1 (ME1) and the consequent increase in NADPH levels play a critical role in this protective mechanism. These results underscore the potential of Glab as a therapeutic agent for addressing PQ poisoning, with particular emphasis on the pivotal role of ME1 in mediating its effects.

Keywords
Apoptosis; Glabridin; Malic enzyme 1; Mitochondrial dysfunction; Oxidative stress; Paraquat; cGAS–STING pathway.
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