The Ketone Body β‐Hydroxybutyrate Mitigates the Ferroptosis of Alveolar Epithelial Cells Type II in Bleomycin‐Induced Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive form of interstitial lung disease and is pathologically featured by excessive deposition of extracellular matrix in response to repetitive epithelial injury. 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 vitro in alveolar epithelial cells type II (AECII) exposed to bleomycin, β-hydroxybutyrate (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-cysteine ligase catalytic subunit (GCLC), the rate-limiting 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-induced 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-based novel approach to therapeutic ketosis for treating IPF.