Long COVID is associated with lipoxygenase-catalyzed metabolism of essential polyunsaturated fatty acids.

Long COVID (LC) represents a failure of healthy resolution mechanisms for inflammation after SARS-CoV-2 infection. Dietary essential polyunsaturated fatty acids (PUFAs) and their downstream metabolites can orchestrate inflammation resolution, suggesting these pathways may be altered in LC. In this study, plasma samples from two independent participant cohorts totaling 106 participants (designated by chart review as LC or Recovered) were collected longitudinally in the 12 months following SARS-CoV-2 infection and analyzed by mass spectrometry for targeted PUFA metabolites. In the acute phase of SARS-CoV-2 infection, upregulation of PUFA metabolites downstream of 12-lipoxygenase was associated with later development of LC. In the months following infection, LC participants displayed uncoupling of PUFA-related lipid metabolism and altered lipoxygenase-driven metabolism over time compared to recovered participants. These results provide new mechanistic insights for the development of LC and suggest potential therapeutic strategies for this prevalent and debilitating disorder.