Chatterjee, T.; Machado, S.; Cowen, K.; Miller, M.; Zhang, Y.; Volpicelli-Daley, L.; Fielding, L.; Pattanayak, R. P.; Rosenblum, F.; Potor, L.; Balla, G.; Balla, J.; Faul, C.; Zarjou, A.

This study explored the role of myeloid ferritin heavy chain (FtH) in coordinating kidney iron trafficking in health and disease. Synuclein- (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion (FtH{Delta}/{Delta}). Following kidney injury, FtH{Delta}/{Delta} mice showed worsened kidney function. Transcriptome analysis revealed coupling of FtH deficiency with ferroptosis activation, a regulated cell death associated with iron accumulation. Adverse effects of ferroptosis were evidenced by upregulation of ferroptosis-related genes, increased oxidative stress markers, and significant iron deposition in kidney tissues. This iron buildup in FtH{Delta}/{Delta} kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction. Mechanistically, we establish that monomeric Snca functions as a ferrireductase catalyst, intensifying oxidative stress and triggering ferroptosis. Additionally, Snca accumulates in kidney diseases distinguished by leukocyte expansion across species. These findings position myeloid FtH as a pivotal orchestrator of the FtH-Snca-Spic axis driving macrophage reprogramming and kidney injury.