12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. The severe disease outcomes are often associated with a hyperinflammatory response known as a "cytokine storm." The mechanisms underlying this exaggerated immune response remain incompletely understood. This study aimed to investigate the molecular pathways contributing to the severe inflammatory damage and mortality associated with COVID-19. SARS-CoV-2 hijacks host lipid metabolism, particularly the phospholipase A2 (PLA2) pathway, leading to the production of bioactive lipid mediators, including 12-lipoxygenase (12-LOX)-derived lipid mediators in platelets, and in lung and vascular cells. We hypothesized that 12-LOX drives the hyperinflammatory response and disease severity, and that its inhibition could reduce inflammation and improve outcomes. Analysis of autopsy lung samples from COVID-19 decedents and SARS-CoV-2-infected K18-hACE2 transgenic mice revealed increased 12-LOX expression. We evaluated VLX-1005, a selective small-molecule 12-LOX inhibitor, in infected mice. Treatment initiated 48 h post-infection significantly improved survival, reduced body weight loss, and decreased lung inflammation compared to controls. Notably, male mice showed higher survival rates than females. VLX-1005 treatment also suppressed key chemokines and cytokines associated with the cytokine storm, and reduced lung damage. These findings identify 12-LOX as a critical mediator of the hyperinflammatory response in severe COVID-19 and support its inhibition as a promising therapeutic strategy to mitigate inflammatory damage and reduce mortality. IMPORTANCE: This study provides critical insights into the mechanisms underlying severe COVID-19, identifying 12-lipoxygenase (12-LOX) as a key driver of the hyperinflammatory response that contributes to disease severity and mortality. By demonstrating that SARS-CoV-2 hijacks host-lipid metabolism to elevate proinflammatory lipid mediators, the research uncovers a novel pathogenic pathway that exacerbates lung inflammation. The use of VLX-1005, a selective 12-LOX inhibitor, significantly improved survival and reduced inflammatory damage in a mouse model, highlighting its therapeutic potential. These findings not only deepen our understanding of COVID-19 pathogenesis but also position 12-LOX as a promising intervention target, offering a new avenue to mitigate the effects of cytokine storms in severe cases.