Myeloid FtH Regulates Macrophage Response to Kidney Injury by Modulating Snca and Ferroptosis

Abstract

This study explored the role of myeloid ferritin heavy chain (FtH) in coordinating kidney iron trafficking in health and disease. Synuclein-α (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion (FtH ^Δ/Δ ). 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, increased oxidative stress markers, and 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. 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.

Highlights: Myeloid FtH deficiency drives kidney injury via activation of ferroptosisMΦ FtH deficiency induces Snca, linking iron dysregulation to MΦ function and response to kidney injuryFerrireductase activity of monomeric Snca augments oxidative stress, promoting lipid peroxidation and ferroptosis.

In brief: MΦ FtH modulates Snca and Spic to coordinate the injury response, linking iron trafficking to ferroptosis-induced kidney injury.