Characterization of dipyridamole as a novel ferroptosis inhibitor and its therapeutic potential in acute respiratory distress syndrome management

These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.

A screening of 259 FDA-approved drugs was conducted to identify an effective ferroptosis inhibitor in pulmonary epithelial and endothelial cells. The anti-ferroptotic and therapeutic efficacy of this screened drug was rigorously evaluated using two distinct ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). The regulatory mechanism of this drug on ferroptosis inhibition was investigated via RNA-sequencing, qRT-PCR, western blotting, IF, luciferase reporter assay, chromatin immunoprecipitation assay, limited proteolysis-mass spectrometry assay, cellular thermal shift assay, and drug affinity responsive target stability assay. Furthermore, a proof-of-concept clinical trial was conducted, wherein ARDS patients were administered with the drug as adjunctive therapy.

Dipyridamole (DIPY) was identified as a potent inhibitor of ferroptosis in pulmonary epithelial and endothelial cells. DIPY effectively mitigated ferroptosis and pulmonary damage in both mouse models and hAOs, primarily by downregulating heme oxygenase 1 (HMOX1). The transcription factor cAMP responsive element binding protein 1 (CREB1) was identified as a key transactivator of HMOX1, which DIPY effectively downregulated. Mechanistically, DIPY binds to and activates superoxide dismutase 1 (SOD1), which in turn inhibits the CREB1/HMOX1 pathway, thereby suppressing ferroptosis. Notably, the clinical trial further corroborated the therapeutic potential of DIPY in ARDS patients, demonstrating improved outcomes with DIPY adjunctive therapy. Conclusions: These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.