Empagliflozin alleviates iron accumulation and ferroptosis to mitigate bleomycin-induced pulmonary fibrosis through TFEB-mediated regulation of ACSL4 and GPX4
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease. It is currently difficult to treat, with limited treatment options available. Recent evidence implicates ferroptosis-an iron-dependent form of regulated cell death-as a critical pathogenic mechanism in pulmonary fibrogenesis. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have been proven to have anti-fibrotic effects on various organ systems, however, there are few studies on the mechanism of action of the drug in pulmonary fibrosis. Utilizing a bleomycin-induced murine model and MLg fibroblasts/MLE12 alveolar epithelial cells, we conducted multi-parametric assessment of fibrotic markers (Alpha smooth muscle actin (α-SMA), Collagen I), ferroptosis markers (intracellular iron, lipid peroxidation), and key regulatory proteins. Empagliflozin treatment significantly attenuated pulmonary collagen deposition and myofibroblast activation in vivo, while demonstrating dual anti-ferroptotic effects in vitro: reducing excessive iron accumulation and lipid peroxidation in MLg cells, while restoring glutathione peroxidase 4 (GPX4) expression in ferroptosis-sensitive MLE12 cells. Mechanistically, empagliflozin upregulates the expression of transcription factor EB (TFEB) post TGF-β1 challenge, initiating coordinated regulation of ferroptosis mediators. TFEB knockdown exacerbated ferroptosis through GPX4 suppression and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) induction,…
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