Yutang Li ¹ Li Tang ² Fang Wang ³ Chencheng Gao ³ Qi Yang ³ Liyu Luo ⁴ Jiahang Wei ⁵ Qiuyun Tang ⁶ Mingran Qi ^3*

• ¹ First Affiliated Hospital of Jilin University, Changchun, Jilin Province, China
• ² Second Affiliated Hospital of Jilin University, Changchun, Jilin Province, China
• ³ Department of Pathogen Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
• ⁴ Beijing Sport University, Beijing, Beijing Municipality, China
• ⁵ Third Hospital of Jilin University, Changchun, Jilin Province, China
• ⁶ Chicheng Town Public Health Center, Suining, China

Acute Respiratory Distress Syndrome (ARDS) poses a significant health challenge due to its high incidence and mortality rates. The emergence of SARS-CoV-2 has added complexity, with evidence suggesting a correlation between COVID-19 induced ARDS and post-COVID symptoms. Understanding the underlying mechanisms of ARDS in COVID-19 patients is crucial for effective clinical treatment. To investigate the potential role of ferroptosis in SARS-CoV-2 induced ARDS, we conducted a comprehensive analysis using bioinformatics methods. Datasets from the Gene Expression Omnibus (GEO) were utilized, focusing on COVID-19 patients with varying ARDS severity. We employed weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and single-cell sequencing to identify key genes associated with ferroptosis in ARDS. Hub genes were validated using additional GEO datasets. The analysis discerned 916 differentially expressed genes in moderate/severe ARDS patients compared to non-critical individuals. Weighted Gene Co-expression Network Analysis (WGCNA) unveiled two modules that exhibited a positive correlation with ARDS, subsequently leading to the identification of 15 hub genes associated with ferroptosis. Among the noteworthy hub genes were MTF1, SAT1, and TXN. Protein-protein interaction analysis, and pathway analysis further elucidated their roles. Immune infiltrating analysis highlighted associations between hub genes and immune cells. Validation in additional datasets confirmed the upregulation of MTF1, SAT1, and TXN in SARS-CoV-2-induced ARDS. This was also demonstrated by qRT-PCR results in the BEAS-2B cells vitro model, suggesting their potential as diagnostic indicators. This study identifies MTF1, SAT1, and TXN as hub genes associated with ferroptosis in SARS-CoV-2-induced ARDS. These findings provide novel insights into the molecular mechanisms underlying ARDS in COVID-19 patients and offer potential targets for immune therapy and targeted treatment. Further experimental validation is warranted to solidify these findings and explore therapeutic interventions for ARDS in the context of COVID-19.