Abstract Chronic kidney disease (CKD) is a worldwide public health problem affecting ~850 million people including 37 million Americans. Advanced CKD results in a number of adverse clinical outcomes leading to high rates of mortality, morbidity, and healthcare expenditure. Recognizing these staggering challenges, the Department of Health and Human Services initiated the “Advancing American Kidney Health (AAKH)” through Executive Order in July 2019. Derangements in iron metabolism are a hallmark of advanced CKD, however, the mechanistic underpinnings of such perturbations and their clinical impact on the course of CKD are not fully understood. The overall goal of this project is to fill the current gaps in knowledge and address this unmet need for the development of novel therapeutic interventions by targeting iron metabolism to slow progression of CKD and delay the need for kidney replacement therapy, two of the major goals of the AAKH initiative. By conducting preliminary studies, we have discovered that macrophage ferritin heavy chain (FtH) diminishes development and progression of CKD. Guided by our findings we propose the unifying hypothesis that myeloid FtH orchestrates iron distribution and regulates macrophage plasticity under injurious/inflammatory conditions. This premise is substantiated by (i) significant upregulation of Spic, a lineage-defining transcription factor that selectively controls development of iron recycling macrophages and (ii) marked elevation and aggregation of synuclein-alpha (Snca), a common pro-inflammatory factor in neurodegenerative conditions in in two models of CKD with substantially higher levels observed in kidneys of mice with targeted deletion of FtH in myeloid compartment. To confirm our hypothesis, we will execute the following specific aims: Aim 1: To test the hypothesis that myeloid FtH regulates monocyte/MΦ differentiation towards iron recycling phenotype through controlling transcription factor Spic. Aim 2: To test the hypothesis that myeloid FtH establishes disease tolerance to CKD via suppression of Snca. Successful completion of the proposed aims will have a significant impact on our understanding of the individual and collective effects of myeloid FtH, Spic and Snca expression in iron handling by the kidney and their detailed connotative roles in the pathogenesis of CKD, thereby paving the way for a new therapeutic approach in this disease by targeting iron metabolism in CKD.