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, Hong‐Xiang Lou, Ting Dong
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. Hemolysis heightens susceptibility to lung injury and predicts poor outcomes in hemolytic disorders. Here, the authors show that MFSD7C shields the lung from hemolysis-related ferroptosis by stabilizing mitochondrial function and regulating GPX4 and ACSL4 expression to prevent lipid peroxidation.