The role of NCOA4-mediated ferritinophagy in ozone-induced pulmonary ferroptosis

The National Heart, Lung, and Blood Institute awarded The Ohio State University $156,080 on February 19, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct research into the role of NCOA4-mediated ferritinophagy in ozone-induced pulmonary ferroptosis.

The research investigates mechanisms by which ground-level ozone exposure induces pulmonary injury and inflammation. Preliminary data indicate that acute ozone inhalation increases lung tissue gene expression of nuclear receptor coactivator 4 (NCOA4), which facilitates intracellular degradation of ferritin, an iron-sequestering protein. The work examines how this NCOA4-mediated ferritinophagy contributes to ozone-induced increases in airspace iron and whether altered lipid biochemistry and iron accumulation trigger ferroptosis—a form of programmed cell death driven by iron overload and lipid peroxidation. The research is intended to clarify the mechanisms linking pulmonary iron dysregulation to ozone-induced adverse pulmonary effects.

Performance occurs at Columbus, Ohio. The award period runs through September 29, 2026. The project grant is classified as assistance funding supporting basic research in cardiovascular and pulmonary disease mechanisms.

Abstract

Ground-level ozone (O3) exposure is a significant global health concern of increasing importance. Annually, an estimated 1 million premature deaths are attributable to O3 exposure, costing the global economy billions of dollars (USD). As global O3 concentrations continue to rise, these significant health and economic burdens are expected to increase. O3 exposure is associated with increased morbidity and mortality of pulmonary diseases. Thus, IT is imperative to identify mechanisms by which O3 induces adverse pulmonary effects. IT is understood that acute O3 inhalation induces pulmonary injury and inflammation mediated in part by the accumulation of airspace iron. However, what remains unclear are the mechanisms by which O3 induces this dysregulation of pulmonary iron homeostasis and the mechanisms by which this iron accumulation mediates pulmonary injury and inflammation. Preliminary data presented in this proposal indicate that O3 increases lung tissue gene expression of nuclear receptor coactivator 4 (NCOA4), which is known to facilitate the intracellular degradation of the iron sequestering protein, ferritin. Moreover, preliminary results show that O3 reduces airspace ferritin concentrations. Combined, these data strongly suggest that acute O3 inhalation induces pulmonary NCOA4- mediated ferritinophagy, which may contribute to O3-induced increases in airspace iron. Additional preliminary data reveals that O3-induced lung injury, inflammation, and cytotoxicity correspond with increased concentrations of lipid ozonation products. Altered lipid biochemistry and increased iron concentrations are favorable conditions for the induction of ferroptosis, a programmed cell death driven by iron overload and lipid peroxidation. Potential for O3-induced ferroptosis is supported by preliminary data indicating O3 alters lung tissue expression of genes associated with induction and progression of ferroptosis. Both ferritinophagy and ferroptosis have been implicated in multiple pulmonary disease etiologies. However, IT is uncertain what role these mechanisms play in O3-induced pulmonary injury and inflammation. This proposal will investigate the hypothesis that NCOA4- mediated ferritinophagy drives O3-induced ferroptosis and subsequent pulmonary inflammation and injury through completion of two aims. These aims will: 1) assess the role of NCOA4 in O3-induced pulmonary ferritinophagy; and 2) examine the effect of cell-specific ferroptosis on O3-induced pulmonary injury and inflammation. Completion of these aims will elucidate novel pathways in pulmonary diseases exacerbated by O3 exposure, with potential for identifying therapeutic targets. Now more than ever, this research is critical to reducing global health and economic burdens associated with O3. Additionally, completing these aims will support the proposed training program and provide the applicant with the necessary tools to become a successful independent scientist researching environmental lung disease: 1) advanced laboratory techniques; 2) a strong scientific network; 3) leadership experience; 4) scientific writing skills; and 5) ethical and collaborative research expertise.