MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis

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 unknown. Here, we report that major facilitator superfamily domain containing 7C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency leads to mitochondrial dysfunction and lipid remodeling caused by increased fatty acid uptake and decreased consumption, the excess accumulation of lipids sensitizes cells to peroxidation and ferroptosis. Moreover, systematic delivery of MFSD7C mRNA-loaded nanoparticles to the lungs effectively prevented lung injury in mice with hemolysis. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders. Overall design: In the present work, we investigated the role and the underlying mechanism of MFSD7C in lung damage in a hemolytic mouse model. We found that MFSD7C protected the pulmonary cells from ferroptosis by stabilizing mitochondrial function and preventing lipid remodeling. MFSD7C knockout alleviated pulmonary inflammation and lung fibrosis by encouraging ferroptosis in the lung. The administration of MFSD7C mRNA-loaded nanoparticles effectively improved lung damage in hemolytic mice model.