Targeting macrophage ferritin heavy chain mitigates ferroptosis and lung injury in experimental acute respiratory distress syndrome
Abstract Ferritin, composed of heavy chain (FTH1) and light chain (FTL) subunits, is a key intracellular iron storage protein, but the origin and biological role of extracellular ferritin (ex-ferritin) remain poorly understood. Elevated serum ex-ferritin is associated with worse outcomes in acute respiratory distress syndrome (ARDS). Here, we show that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AM) of individuals with ARDS, findings we replicate in a murine hyperoxia-induced acute lung injury model. Myeloid-specific FTH1 ( Fth1 ΔLysM ) deletion attenuates lung injury, and is associated with reduced macrophage ferroptosis, altered airway inflammatory responses, lower extracellular iron and compensatory secretion of FTL-ex-ferritin. While pharmacologic ferroptosis inhibition prior to hyperoxia had no effect, transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid conferred protection from lung injury. These findings identify macrophage ferritin metabolism and ex-ferritin secretion as critical regulators of lung injury, offering new insights into the pathobiology of ARDS.
Authors
- Cem Meydan (ORCID: https://orcid.org/0000-0002-0663-6216)
- Sarah R. Walmsley (ORCID: https://orcid.org/0000-0001-9584-174X)
- Lynne Faherty (ORCID: https://orcid.org/0000-0002-9494-084X)
- Sebastian E. Carrasco (ORCID: https://orcid.org/0000-0002-1926-7296)
- Augustine M.K. Choi (ORCID: https://orcid.org/0000-0002-4836-305X)
- Parag Goyal (ORCID: https://orcid.org/0000-0001-7474-3737)
- Chia‐Lang Hsu (ORCID: https://orcid.org/0000-0002-7447-8045)
- David Redmond (ORCID: https://orcid.org/0000-0002-0983-8606)
- Sean Houghton (ORCID: https://orcid.org/0000-0001-6385-006X)
- Divya Bhatia (ORCID: https://orcid.org/0000-0002-8236-3440)
- Eleni Kallinos (ORCID: https://orcid.org/0000-0002-6666-4016)
- Suzanne M. Cloonan (ORCID: https://orcid.org/0000-0001-5301-9926)
- Will Simmons
- Ananda S. Mirchandani (ORCID: https://orcid.org/0000-0002-5492-1687)
- Kuei‐Pin Chung (ORCID: https://orcid.org/0000-0003-1916-8068)
- Karla V. Ballman (ORCID: https://orcid.org/0000-0002-4492-0357)
- Joseph Douglas Mancias (ORCID: https://orcid.org/0000-0002-0692-3717)
- William Z. Zhang (ORCID: https://orcid.org/0000-0002-3017-009X)
- Christopher E. Mason (ORCID: https://orcid.org/0000-0002-1850-1642)
- Edward James Schenck (ORCID: https://orcid.org/0000-0002-7950-5989)
- Kihwan Kim (ORCID: https://orcid.org/0000-0003-0257-1707)
- Leora Haber
- Katherine L. Hoffman
- Maria Plataki
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- National Taiwan University (TW)
- Trinity College Dublin (IE)
- Cornell University (US)
- Tallaght University Hospital (IE)
- Dana-Farber Cancer Institute (US)
- National Taiwan University Hospital (TW)
- Centre for Inflammation Research (GB)
- Weill Cornell Medicine (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-27
- DOI
- https://doi.org/10.1038/s41467-026-74828-w
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Parker Foundation
- Science Foundation Ireland
- Irish Research Council
- National Heart, Lung, and Blood Institute