Ferroptosis-pyroptosis crosstalk signature as prognostic biomarkers and therapeutic targets in sepsis-induced ARDS.

Background: Acute respiratory distress syndrome (ARDS) is a severe complication of sepsis with high mortality. Ferroptosis and pyroptosis are two distinct forms of regulated cell death that have been implicated in sepsis-induced organ dysfunction. However, the crosstalk between these 2 cell death pathways in sepsis-induced ARDS remains unclear. Methods: We analyzed gene expression data from sepsis and ARDS patients to identify ferroptosis-pyroptosis crosstalk genes. Single-cell RNA sequencing was performed to characterize cell type-specific expression patterns. Gene expression was validated using quantitative PCR and ELISA assays. Pathway enrichment analysis and protein-protein interaction networks were constructed to elucidate the molecular mechanisms. Results: We identified 10 ferroptosis-pyroptosis crosstalk genes with differential expression between ARDS and sepsis-only groups. Key genes including GPX4, GSDMD, SLC7A11, and CASP1 showed significant dysregulation in ARDS. Single-cell analysis indicated heterogeneous expression across immune cell populations, with enrichment of selected signals in myeloid cells. Pathway analysis indicated enrichment in inflammatory response, oxidative stress, and cell death pathways. PCR and ELISA validation confirmed the differential expression of these biomarkers. Conclusion: Ferroptosis-pyroptosis crosstalk genes serve as potential prognostic biomarkers and therapeutic targets in sepsis-induced ARDS. The identified gene signature provides insights into the pathophysiology and may guide the development of targeted interventions.