Abstract: Open access Editorial James J DiNicolantonio ‍ ‍,1 Mark McCarty,2 Jorge Barroso-­Aranda3 To cite: DiNicolantonio JJ, McCarty M, Barroso-­Aranda J. Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections. Open Heart 2021;8:e001568. doi:10.1136/ openhrt-2020-001568 Accepted 22 February 2021 © Author(s) (or their employer(s)) 2021. Re-­use permitted under CC BY-­NC. No commercial re-­use. See rights and permissions. Published by BMJ. 1 Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA 2 Catalytic Longevity, Encinitas, California, USA 3 Clinica Libre de Adicciones, Tijuana, Mexico Correspondence to Dr James J DiNicolantonio; ​ jjdinicol@​gmail.​com ABSTRACT 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. MELATONIN SUPPLEMENTATION MAY REDUCE RISK FOR COVID-19 A retrospective analysis of 791 intubated patients with COVID-19 has found that, after adjustment for pertinent demographics and comorbidities, those treated with melatonin had a markedly lower risk for mortality (HR: 0.131, 95% CI: 0.076 to 0.223)—suggestive of a profound anti-­inflammatory benefit.1 Such an effect might be anticipated, in light of melatonin’s ability to upregulate expression of silent information regulator 1 (Sirt1)—a deacetylase that is known to suppress the activity of the proinflammatory nuclear factor kappa B (NF-­kappaB) transcription factor— and also upregulate nuclear factor erythroid 2-­ related factor 2 (Nrf2), which promotes the transcription of a range of antioxidant proteins.2–4 Moreover, recent epidemiology suggests that melatonin usage may reduce the risk for contracting COVID-19. A recent retrospective study, examining data from 26 799 subjects in a COVID-19 registry and using propensity score matching to account for a range of covariates, found that current supplementation with melatonin was associated with a significant 28% reduction in risk for serologically detectible COVID-19 infection. Among Black Americans, this reduction in risk was a remarkable 52% (OR=0.48, 95% CI 0.31 to 0.75).5 The basis of this decrease in risk for COVID-19 is unclear, especially since Sirt1 activity, which melatonin promotes, is known to transcriptionally upregulate expression of ACE2—the cellular membrane receptor for COVID-19.6 7 MELATONIN-INDUCED SIRT1 MAY BOOST VIRALLY..