Characterization of Dipyridamole as a Novel Ferroptosis Inhibitor and its Therapeutic Potential in Acute Respiratory Distress Syndrome Management

Ferroptosis in lung epithelium and endothelium contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), a critical and frequently fatal condition marked by acute inflammation and elevated pulmonary vascular permeability. Despite this, there are currently no FDA-approved therapeutics specifically targeting ferroptosis for ARDS management. In this investigation, we identified Dipyridamole (DIPY) as a potent ferroptosis inhibitor in pulmonary epithelial and endothelial cells via screening 259 FDA-approved drugs. The anti-ferroptotic and therapeutic efficacy of DIPY was validated in two ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). To explore the molecular mechanism of DIPY against ferroptosis, we performed RNA-Seq analysis by utilizing RSL3- or RSL3 plus DIPY-treated A549 cells.