| Summary: | A recent retrospective study has provided evidence that COVID-19 infection may be notably less common in those using supplemental melatonin. It is suggested that this phenomenon may reflect the fact that, via induction of silent information regulator 1 (Sirt1), melatonin can upregulate K63 polyubiquitination of the mitochondrial antiviral-signalling protein, thereby boosting virally mediated induction of type 1 interferons. Moreover, Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes. This nuclear retention of HMGB1 may also be a mediator of the anti-inflammatory effect of melatonin therapy in COVID-19—complementing melatonin’s suppression of nuclear factor kappa B activity and upregulation of nuclear factor erythroid 2-related factor 2. If these speculations are correct, a nutraceutical regimen including vitamin D, zinc and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.
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