Background: Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung disease with high mortality and limited effective therapies. Recent studies link ferroptosis—an iron-dependent regulated cell death—to ARDS pathogenesis. This study aimed to identify/validate ferroptosis-related diagnostic biomarkers, therapeutic targets, and fecal microbiota transplantation (FMT)’s protective role in ARDS. Methods: Bioinformatic analyses of GEO datasets (GSE76293/GSE151263) included differential expression profiling, WGCNA, PPI network, and machine learning (LASSO/RF) to screen hub genes, with ROC analysis for diagnostic efficacy. An LPS-induced ARDS rat model with FMT intervention was validated via qRT-PCR, IHC, Western blot, and histological staining. Results: Thirty-seven ferroptosis-linked differentially expressed genes (FDEGs) were identified, enriched in ferroptosis, mitophagy, and immune pathways. Three hub genes (MAPK8, CREB1, GPX4) showed robust diagnostic utility (LASSO AUC=0.931; RF AUC=0.993 in GSE76293) and correlated with monocytes/neutrophils/activated NK cells. LPS suppressed their mRNA/protein levels in rats, reversed by FMT. Conclusion: MAPK8, CREB1, and GPX4 are potential diagnostic biomarkers and therapeutic targets for ARDS. FMT protects against ARDS by reversing these genes’ downregulation and suppressing ferroptosis, providing new insights into ARDS pathogenesis and ferroptosis-targeted interventions. Keywords: acute respiratory distress syndrome, ferroptosis, fecal microbiota transplantation, GPX4, MAPK8, CREB1
Dong et al. (Wed,) studied this question.