Kidney Week

Abstract: FR-PO0223

Myeloid Ferritin Heavy Chain Regulates Macrophage Response to Kidney Injury by Modulating Synuclein-α and Ferroptosis

Session Information

• Anemia and Iron Metabolism
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

• 200 Anemia and Iron Metabolism

Authors

• Chatterjee, Tanima, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Tanima Chatterjee, PhD

• Machado, Sarah Elizabeth, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Sarah Elizabeth Machado, MPH

• Cowen, Kellen A., University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Kellen A. Cowen

• Miller, Mary Elizabeth, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Mary Elizabeth Miller, MS

• Rosenblum, Frida, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Frida Rosenblum, MD

• Faul, Christian, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Christian Faul, PhD

• Zarjou, Abolfazl, University of Alabama at Birmingham Health System, Birmingham, Alabama, United States

Abolfazl Zarjou, MD, PhD, FASN

Background

Acute kidney injury and its progression to chronic kidney disease, are increasingly recognized as a continuum of insults culminating in significant adverse clinical sequelae. Macrophages comprise a heterogenous population with remarkable phenotypic plasticity essential for orchestrating injury responses and regulating iron homeostasis. Ferritin heavy chain (FtH), the principal intracellular iron storage protein endowed with intrinsic ferroxidase activity, catalyzes the oxidation of ferrous iron (Fe²⁺) to its more stable ferric state (Fe³⁺). Given FtH’s paramount role in dictating macrophage iron homeostasis, we sought to delineate the mechanisms by which FtH governs kidney iron trafficking in both health and disease.

Methods

Utilizing myeloid-specific FtH knockout mice (FtH^Δ/Δ) we employed various methodologies including bulk and single cell-RNA sequencing, real-time PCR, Western blotting, flow cytometry, mass spectrometry, and immunohistochemistry to establish the functional significance of myeloid FtH in kidney disease.

Results

Synuclein-α (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion. Following kidney injury, FtH^Δ/Δ 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 and markers of oxidative stress, as well as significant iron deposition in kidney tissues. This iron buildup in FtH^Δ/Δ kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction.

Conclusion

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 insights provide a novel conceptual paradigm, wherein immune-mediated iron metabolism intersects with tissue injury, offering therapeutic targets that could concurrently mitigate kidney disease progression and its potential propagation to the brain, highlighting a possible mechanistic bridge to Parkinson’s disease.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025684gyged