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Given the central role of ferritin heavy chain (FtH) as a molecular rheostat linking iron sequestration to redox-dependent signaling, we examined how myeloid FtH governs renal iron trafficking and ensuing oxidative stress pathways during acute kidney injury (AKI). Transcriptome analysis revealed coupling of FtH deficiency in monocytes and macrophages with activation of ferroptosis, a regulated cell death associated with iron accumulation. Moreover, myeloid FtH deletion worsened AKI, increasing leukocyte infiltration and iron deposition, together with ferroptosis-associated gene induction, oxidative stress, and lipid peroxidation. Notably, \u03b1-synuclein (SNCA), an iron-binding protein and the main pathological driver of Parkinson\u2019s disease, was robustly induced both by FtH deficiency and following AKI. Mechanistic studies showed that monomeric SNCA exhibits ferrireductase activity, amplifying redox cycling and promoting ferroptotic cell death. Furthermore, SNCA expression was elevated in kidney pathologies characterized by leukocyte expansion in both mouse models and human cohorts, suggesting that inflammatory microenvironments promote SNCA accumulation and redox imbalance. These findings define a macrophage FtH\/SNCA regulatory axis as a key driver of ferroptosis in AKI, implicating SNCA as a pathological nexus between iron dyshomeostasis and inflammatory kidney injury.<\/jats:p>","DOI":"10.1172\/jci.insight.196521","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T16:00:13Z","timestamp":1773158413000},"source":"Crossref","is-referenced-by-count":3,"title":["Macrophage ferritin heavy chain\/\u03b1-synuclein regulatory axis modulates ferroptosis during kidney injury"],"prefix":"10.1172","volume":"11","author":[{"given":"Tanima","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Machado","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of 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