MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis

  • Nat Commun. 2024 Sep 19;15(1):8226. doi: 10.1038/s41467-024-52537-6.
Huirui Wang  #  1 ,  Xiaona You  #  2 ,  Jingcheng Wang  #  1 ,  Xinyi Chen  3 ,  Yinghui Gao  1 ,  Mengmeng Wang  1 ,  Wenru Zhang  1 ,  Jiaozhen Zhang  1 ,  Yang Yu  4 ,  Bo Han  5 ,  Mei Qi  6 ,  Xiaohui Liu  7 ,  Hongxiang Lou  8 ,  Ting Dong  9
Affiliations
  • 1. Department of Natural Products Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, Jinan, China.
  • 2. Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
  • 3. Division of Infection and Immunity, University College London, London, USA.
  • 4. Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5. Department of Pathology, Shandong University School of Basic Medical Sciences, Jinan, China.
  • 6. Department of Pathology, Shandong University Qilu hospital, Jinan, China.
  • 7. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 8. Department of Natural Products Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, Jinan, China. [email protected].
  • 9. Department of Natural Products Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, Jinan, China. [email protected].
  • # Contributed equally.
PMID: 39300060 DOI: 10.1038/s41467-024-52537-6
Abstract

Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and Sickle Cell Disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing Ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting Ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C-/- mice. These findings present the detailed link between hemolytic complications and Ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.

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