MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis

Huirui Wang, Xiaona You, Jingcheng Wang, Xinyi Chen, Yinghui Gao, Mengmeng Wang, Wenru Zhang, Jiaozhen Zhang, Yang Yu, Bo Han, Mei Qi, Xiaohui Liu (), Hongxiang Lou () and Ting Dong ()
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Huirui Wang: Shandong University
Xiaona You: Shandong University
Jingcheng Wang: Shandong University
Xinyi Chen: University College London
Yinghui Gao: Shandong University
Mengmeng Wang: Shandong University
Wenru Zhang: Shandong University
Jiaozhen Zhang: Shandong University
Yang Yu: Shandong University
Bo Han: Shandong University School of Basic Medical Sciences
Mei Qi: Shandong University Qilu hospital
Xiaohui Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Hongxiang Lou: Shandong University
Ting Dong: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52537-6

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