12-Lipoxygenase Drives Hyperinflammatory Responses and Enhances COVID-19 Severity 9032

Abstract Description The COVID-19 pandemic remains a significant global challenge, with comorbidities like obesity and diabetes exacerbating the severe outcomes. However, the mechanisms driving heightened susceptibility in these populations are poorly understood. SARS-CoV-2 infection disrupts lipid metabolism pathways regulated by Phospholipase A2 and 12-Lipoxygenase (12-LOX), an enzyme producing pro-inflammatory lipids such as 12-S-hydroxy eicosatetraenoic acid (12-HETE). This study examined the role of 12-LOX in severe COVID-19-associated hyperinflammation and evaluated the therapeutic potential of 12-LOX inhibition. We found elevated 12-LOX expression in lung and pancreatic tissues of diabetic COVID-19 decedents compared to the diabetic individuals with non-COVID-respiratory deaths. In SARS-CoV-2-infected K18-hACE2 mice, 12-LOX expression increased in lung and pancreatic tissues, even without diabetes, mirroring human findings. Treatment with the 12-LOX inhibitor VLX-1005 improved survival in mice receiving high-challenge doses of SARS-CoV-2. VLX-1005 treatment downregulated 30 pro-inflammatory cytokine and chemokine genes while upregulating four anti-inflammatory genes. Treated mice exhibited reduced inflammation and lower viral loads in the lungs. Notably, 12-HETE was undetectable in VLX-1005-treated mice but significantly elevated in controls. These findings demonstrate that 12-LOX inhibition mitigates hyperinflammation and improves survival against severe COVID-19 infection. Funding Sources Veralox Therapeutics funded this research. Topic Categories Viral Immunology (VIR)