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Burgeoning evidence suggests that ketone body exerts a beneficial effect on oxidative stress and on different types of fibrotic diseases, including cardiac fibrosis, hepatic fibrosis, and renal fibrosis. However, its effect on IPF is largely unknown. In\u00a0vitro in alveolar epithelial cells type II (AECII) exposed to bleomycin, \u03b2\u2010hydroxybutyrate (BHB) treatment substantially mitigated cellular ferroptosis, as evidenced by enhanced cell viability, reduced iron content, and reduced lipid peroxidation. This beneficial action of BHB coincided with a reinforced de novo glutathione synthesis and increased glutathione peroxidase 4 (GPX4) antioxidant response. Mechanistically, BHB promoted the expression of glutamate\u2010cysteine ligase catalytic subunit (GCLC), the rate\u2010limiting enzyme in de novo glutathione synthesis. Indeed, RSL3, a selective inhibitor of GPX4, or knockdown of GCLC abolished, whereas selective activation of GPX4 was sufficient for the antiferroptosis and AECII protective effects of BHB. In murine models of bleomycin\u2010induced IPF, BHB therapy promoted the expression of GCLC and reinforced GPX4 activity in AECII, resulting in lessened AECII ferroptosis and improved lung injury and fibrosis. Thus, our findings may pave the way for developing a BHB\u2010based novel approach to therapeutic ketosis for treating IPF.<\/jats:p>","DOI":"10.1096\/fj.202501665r","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T11:04:38Z","timestamp":1754910278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Ketone Body \u03b2\u2010Hydroxybutyrate Mitigates the Ferroptosis of Alveolar Epithelial Cells Type\n                    <scp>II<\/scp>\n                    in Bleomycin\u2010Induced Pulmonary Fibrosis"],"prefix":"10.1096","volume":"39","author":[{"given":"Jian","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Anesthesiology West China Hospital, Sichuan University  Chengdu China"},{"name":"Laboratory of Anesthesia and Critical Care Medicine, National\u2010Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology West China 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