Inhibition of ferroptosis by serine protease inhibitor attenuates acute respiratory distress syndrome.

Summary

Using LPS-induced murine ARDS and endothelial/epithelial cell models, ulinastatin reduced ferroptosis markers, suppressed KEAP1, activated NRF2, restored GPX4, and attenuated lung injury and inflammatory cytokines. Transcriptomics highlighted ferroptosis as a key pathway suppressed by UTI, suggesting a mechanistic link between UTI and KEAP1–NRF2–GPX4-mediated ferroptosis inhibition.

Key Findings

• UTI reduced labile iron, MDA, and lipid ROS and increased GPX4 expression in LPS-induced ARDS models.
• UTI suppressed KEAP1 and activated NRF2, consistent with ferroptosis inhibition.
• RNA-seq identified ferroptosis as a top pathway suppressed by UTI, correlating with reduced lung injury and cytokines.

Clinical Implications

While preclinical, the data support testing ulinastatin in ARDS populations with ferroptosis signatures and incorporating KEAP1–NRF2–GPX4 biomarkers to guide dosing and patient selection.

Limitations

• LPS-induced ARDS may not capture clinical heterogeneity of human ARDS
• Lack of genetic perturbation or biophysical binding confirmation to prove direct KEAP1 targeting

Future Directions

Validate KEAP1 binding biophysically and with genetic models; test efficacy in pneumonia/sepsis ARDS models; design biomarker-guided early-phase clinical trials.