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Background: Acute respiratory distress syndrome (ARDS) / acute lung injury (ALI) is a serious medical disease characterized by pulmonary dysfunction and inflammation. This study aims to determine the main molecular modules linked to ARDS and investigate the role of Fibulin-1 (FBLN1) in regulating ferroptosis in ARDS. Methods: Weighted Gene Co-expression Network Analysis (WGCNA) was employed on the GSE263867 dataset to find key modules associated with ALI. Differentially expressed genes (DEGs) and protein-protein interaction (PPI) networks were analyzed. MLE-12 cells were treated with lipopolysaccharide (LPS) to induce ferroptosis. In vitro studies were conducted to investigate the effects of FBLN1 and Transforming Growth Factor Beta 1 (TGF-β) overexpression on cell viability, oxidative stress markers, and ferroptosis-related proteins. Results: WGCNA identified the turquoise module as significantly negatively correlated with ARDS. Five key overlapping genes (GRIA1, OGN, COL14A1, FBLN1, and COL6A3) were significantly downregulated in ARDS samples. LPS treatment induced ferroptosis in MLE-12 cells, indicated by increased malondialdehyde (MDA), lipid reactive oxygen species (ROS), and ferrous iron (Fe2⁺) levels, and decreased cell viability and glutathione (GSH) levels. FBLN1 overexpression partially reversed these effects. Additionally, FBLN1 inhibited the TGF-β/Smad signaling pathway, as shown by decreased TGF-β and p-Smad protein levels. TGF-β overexpression exacerbated LPS-induced oxidative stress and ferroptosis, reducing cell viability and GSH levels. FBLN1 overexpression counteracted this effect, suggesting antagonistic roles for FBLN1 and TGF-β in regulating ferroptosis. Conclusion: This study highlights FBLN1 as a critical regulator of ferroptosis in ARDS. Targeting the TGF-β/Smad pathway to modulate FBLN1 expression offers a potential therapeutic strategy to alleviate oxidative stress and mitigate pulmonary injury in inflammatory lung diseases. [ABSTRACT FROM AUTHOR]