SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD

Summary

Using human ARDS datasets, LPS-induced mouse models, clinical sera, and LPS-stimulated AT2 cells, the authors show SERPINE1 is markedly upregulated and correlates with severity. Genetic deletion or pharmacologic inhibition of SERPINE1 reduces lung injury and ferroptosis markers (ACSL4, ALOX12) while restoring SLC7A11, GPX4, and FTH1. Mechanistically, SERPINE1 interacts with complex I subunit NDUFB10 to perturb mitochondrial NAD/NADH homeostasis and Sirt3 signaling, thereby driving ferroptosis.

Key Findings

• SERPINE1 is markedly upregulated in ARDS patients, ARDS mouse lungs, and LPS-treated AT2 cells and correlates with disease severity.
• SERPINE1 deficiency or pharmacologic inhibition reduces lung injury, suppresses ferroptosis markers (ACSL4, ALOX12), and restores anti-ferroptotic proteins (SLC7A11, GPX4, FTH1).
• Mechanistically, SERPINE1 interacts with complex I subunit NDUFB10 to disrupt mitochondrial NAD/NADH homeostasis and Sirt3 signaling, thereby driving epithelial ferroptosis.

Clinical Implications

SERPINE1/PAI-1 inhibition and ferroptosis-modulating strategies could be explored as targeted therapies in ARDS; SERPINE1 may serve as a biomarker to identify ferroptosis-high endotypes for precision interventions.

Limitations

• Preclinical nature without interventional human trials to confirm therapeutic benefit
• Potential model-specific effects and uncertainty about optimal dosing/timing for PAI-1 inhibitors in humans

Future Directions

Translate SERPINE1-targeted or ferroptosis-modulating therapies into early-phase clinical trials with endotype selection and ferroptosis biomarkers; dissect cell type–specific roles and safety of chronic modulation.