2. Academic Validation
  3. Leonurine alleviates lung ischemia-reperfusion injury through suppression of ferroptosis via RORα in male mice

Leonurine alleviates lung ischemia-reperfusion injury through suppression of ferroptosis via RORα in male mice

  • J Endocrinol. 2026 Jan 19;268(1):e250298. doi: 10.1530/JOE-25-0298.
Wanying Chen 1,  Li Yang 2,  Yincong Xue 3,  Yuting Zhang 4,  Chengshui Chen 4 5 6,  Shuai Huang 6
Affiliations

Affiliations

  • 1 Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
  • 4 Zhejiang Province Engineering Research Center for Endoscope Instruments and Technology Development, Quzhou, China.
  • 5 Department of Pulmonary and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China.
  • 6 Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
PMID: 41498500 DOI: 10.1530/JOE-25-0298
Abstract

Lung ischemia-reperfusion injury (LIRI) is a complex pathological condition that significantly impairs clinical outcomes following lung transplantation and thoracic surgery. Leonurine (LEO), an alkaloid derived from Leonurus japonicus, which has known anti-inflammatory and antioxidant properties, has shown therapeutic potential in various oxidative stress-related diseases. However, the effects of LEO on LIRI and its underlying mechanisms remain unclear. In the present study, a murine model of LIRI was established using wild-type mice. LEO treatment significantly improved lung histopathology, reduced oxidative stress, decreased pulmonary edema, and enhanced survival. Bioinformatics analyses - including volcano plot, KEGG enrichment, and GSEA - identified Ferroptosis as a key regulatory pathway. In vivo and in vitro assays (HE, 4-HNE, and DHE labeling; immunofluorescence; and immunoblotting) confirmed that LEO inhibited Ferroptosis in lung tissue and in MLE-12 cells. Mechanistically, LEO upregulated the RORα/Nrf2/GPX4 axis, thereby reducing lipid peroxidation and iron overload, as validated by BODIPY581/591 C11 and FeRhoNox-1 staining. Moreover, RORα inhibition abolished the anti-ferroptotic effects of LEO, indicating that its protective function is RORα dependent. Molecular docking further supported a potential direct interaction between LEO and RORα. Collectively, LEO alleviates LIRI by inhibiting Ferroptosis through activation of the RORα/Nrf2/GPX4 signaling pathway. These findings suggest that LEO may serve as a promising therapeutic agent for the treatment of LIRI.

Keywords

RORα; ferroptosis; leonurine; lung ischemia–reperfusion injury.

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