Myeloid FtH deficiency accelerates kidney disease by inducing Snca and ferroptosis

This study aimed to investigate impact of myeloid ferritin heavy chain (FtH) deletion on iron trafficking in kidney health and disease. Myeloid FtH deletion (FtH?/?) led to upregulation of synuclein-a (Snca) as the only iron-binding protein. When exposed to kidney injury, FtH?/? mice exhibited significantly worse kidney function. Transcriptome analysis identified ferroptosis as a key pathway triggered by FtH deletion. This was confirmed by elevated expression of ferroptosis-related genes, oxidative stress markers, and increased iron deposition in the kidneys. The latter was mediated via reprogramming of macrophages to an iron-recycling phenotype by inducing Spic. Mechanistically, we demonstrate ferrireductase activity of monomeric Snca acts as a catalyst triggering oxidative stress and ferroptosis. Moreover, kidney accumulation of Snca is promoted in kidney diseases marked by heavy leukocyte infiltration in both mice and humans. These findings emphasize role of FtH in regulating iron metabolism and promoting kidney repair by suppressing Snca and Spic. Overall design: Male FtHfl/fl and FtH?/? mice (8–10 weeks old) were randomly assigned to either the aristolochic acid (AA) injection group or the control (Saline) group. Mice in the AA group received intraperitoneal injections of AA (2 mg/kg body weight; Sigma-Aldrich, A9451) once daily for five consecutive days to induce kidney injury, while control mice received an equal volume of saline as a vehicle control. Mice were harvested at Weeks 6 post-final injection, and CD45? immune cells were sorted from kidneys using flow cytometry and subjected to scRNA-seq using the 10× Genomics platform.