The COVID-19 death toll has involved to date more than 1 million confirmed deaths. The death rate is even higher in the obese COVID-19 patients, as a result of hypoxia, due to the interplay between adipose tissue hypoxia and obstructive sleep apnea. The discrepancy of manifestations seen in COVID-19 seems to be mediated by a differential immune response rather than a differential viral load. One of the key players of the immune response is HIF. HIF-1ß is a stable constitutively expressed protein in the nucleus; and under hypoxic changes, its activity is unaffected, whereas the HIF-&#945; subunit has a short half-life and because of its degradation by an enzyme known as propyl hydroxylase; under hypoxic conditions, propyl hydroxylase gets deactivated thus leading to the stabilization of HIF-1&#945;. As mentioned before, HIF-1&#945; expression is triggered by hypoxic states, this crippling condition will aggravate the pro-inflammatory characteristics of HIF-1&#945;. The vast majority of decompensated COVID19 cases manifest with drastic lung injury and severe viral pneumonia, the infection-induced hypoxia will the existing hypoxia in obesity. This will additionally augment HIF-1&#945; levels that will provoke the already existing cytokines' storm to fulminant. Consequently, this will directly correlate the effect of a hypoxic environment with the increase of HIF-1&#945; level. HIFÉ exists in two main isoforms HIF-1&#945; and HIF-2&#945;. HIF-1&#945; and HIF-2&#945; act in distinct ways in how they work on different target genes. For example, HIF-2&#945; may act on hemopoietin genes (heme-regulating genes); while HIF-1&#945; acts on EPO. HIF-1&#945; release seems to be markedly augmented in obesity due to adipose tissue hypoxia and obstructive sleep apnea resulting in cyclic hypoxia. HIF-1&#945; can also be secreted by direct viral proteolytic effects. Whereas, HIF-2&#945; is stimulated by chronic hypoxia. HIF-1&#945; exerts detrimental effects on the immune system, characterized by unopposed pro-inflammation at the macrophages, dendritic cells, T cells, and complement levels resulting in cytokines' storm, which is linked to the poor outcomes of COVID-19. On the other hand, HIF-2&#945; role is regulatory and largely opposes the actions mediated by HIF-1&#945;. In view of this, inhibiting HIF-1&#945; release or switching its production to HIF-2&#945; by natural products such as resveratrol or by synthetic drugs, offer a good therapeutic strategy that can prevent COVID-19 worst outcome in infected patients. The approach of breaking the vicious circle between lung damage-induced hypoxia and HIF-1&#945; pro-inflammatory stimulant through drugs is considered to be extremely promising as a therapeutic manner to combat further deterioration of COVID19 cases.
Hypoxia-inducible factor (HIF): The link between obesity and COVID-19