Based on our current understanding of the genome of the SARS-CoV-2 and its antigenic components, efforts are being made to develop specific anti-viral drugs, vaccines, and antibody therapies (including plasma therapy). All these efforts take time to come to the clinic. In this context, it is noteworthy that little attention has been paid to the potential role of bioactive lipids (BALs) in COVID-19. Previously, I proposed that bioactive lipids, such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and their metabolites, such as pro-inflammatory prostaglandins (PGs), leukotrienes (LTs), anti-inflammatory lipoxin A4 (LXA4, derived from AA), resolvins (derived from EPA and DHA), protectins, and maresins (derived from DHA) may have a significant role in COVID-19 [16
]. This proposal is based on the observations that AA and other BALs (i) can inactivate enveloped viruses, such as HCV, HBV, influenza, and other corona species; (ii) have the ability to facilitate the generation of M1 and M2 macrophages (M1 by pro-inflammatory BALs, such as PGs and LTs, and M2 by anti-inflammatory BALs, such as LXA4, resolvins, protectins, and maresins); (iii) suppress the production of IL-6, TNF-α and other pro-inflammatory cytokines especially by AA/EPA/DHA, PGE2, and LXA4 and enhance the formation of IL-10 by LXA4; (iv) AA/EPA/DHA/PGE1/LXA4 have cytoprotective actions and, thus, protect normal cells from both endogenous and exogenous toxins including viruses; (v) AA/EPA/DHA/LXA4/resolvins, protectins, and maresins have vasodilator, platelet anti-aggregator actions and suppress leukocyte activation, adherence, and their ability to release free radicals, and finally (vi) BALs especially LXA4, resolvins, protectins, and maresins resolve inflammation and enhance wound healing [20
]. Thus, availability, formation, and release of appropriate amounts of AA/EPA/DHA (especially AA) and maintenance of a balance between pro- and anti-inflammatory BALs is expected to be of benefit in the prevention and amelioration of COVID-19. Of all the BALs, AA seems to be of significant benefit in this context, since it forms the precursor to both pro-inflammatory PGE2 and anti-inflammatory LXA4. The balance between PGE2 and LXA4 is needed to maintain normal homeostasis so that inappropriate inflammatory events do not occur due to an excess of PGE2 and/or deficiency of LXA4 that could lead to severe illness. Hence, factors that regulate the formation of PGE2 and LXA4, such as desaturases, PLA2 activity that is needed for its (AA) release from the cell membrane lipid pool, activities of cyclo-oxygenase-2 (COX-2) and lipoxygenases (LOXs) that are essential for the conversion of AA to PGE2 and LXA4, and their degradation enzymes, such as 15-PGDH, have a critical role in COVID-19 [17
]. Furthermore, AA has cytoprotective actions [24
] (which especially protects vascular endothelial and neuronal cells), suppresses platelet and leukocyte activation, and thus, prevents thromboembolic complications seen in COVID-19.This proposal implies that a deficiency of AA (and EPA and DHA; AA > EPA ≥ DHA) may enhance the susceptibility of an individual to SARS-CoV-2 infection and administration of these fatty acids may enhance the recovery process. This is supported by the reports that human cells infected with coronavirus release large amounts of AA and LA, and these fatty acids inactivate the virus [26
]. Previously, we showed that patients with type 1 and type 2 diabetes mellitus, hypertension, coronary heart disease, and insulin resistance have AA deficiency [28
]. This accounts for the high degree of mortality seen in these patients when they develop COVID-19.