Background: Acute lung injury (ALI) involves severe inflammation and oxidative stress. Ferroptosis, a regulated form of cell death, and immune cell infiltration are increasingly recognized as central mechanisms in ALI. Methods: This study integrated transcriptomic and miRNA datasets from GEO with ferroptosis-related gene sets from FerrDb. Differential expression, enrichment analyses, WGCNA, ssGSEA, and PPI network construction were applied to identify key genes. Experimental validation was performed in a murine LPS-induced ALI model using qRT-PCR, Western blotting, lung injury assessment, and ferroptosis marker analysis. In addition, a dual-luciferase reporter assay was conducted to verify the direct binding of miR-21a-5p to the EGR1 3 ' UTR. Results: Twenty-two ferroptosis-related genes were differentially expressed and enriched in inflammation and IL17 signaling. Five key genes (IL6, IL1B, TIMP1, ATF3, and EGR1) were identified by intersecting PPI and WGCNA results. EGR1 was positively correlated with immune infiltration and validated as significantly upregulated in LPS-induced ALI. Knockdown of EGR1 mitigated ferroptosis, reduced ROS, MDA, and iron accumulation, restored GPX4, SLC7A11, and FTH1 expression, and improved lung function. Erastin, a ferroptosis inducer, reversed the protective effects. A miRNA-mRNA network suggested mmu-miR-21a-5p regulates EGR1, and dualluciferase reporter assays further confirmed the direct binding of miR-21a-5p to the EGR1 3 ' UTR. Conclusion: EGR1 is a central regulator linking ferroptosis and immune cell infiltration in LPS-induced ALI. Targeting the miR-21a-5p-EGR1 axis may offer novel diagnostic and therapeutic strategies for acute lung injury.