Abstract. The widespread COVID-19 pandemic has been, currently, converted to a catastrophic human health challenge. Vitamin D (VD) and its metabolites have been used as a palliative treatment for chronic inflammatory and infectious diseases from ancient times. In the current study, some molecular aspects of the potential effects of VD against COVID-19 side-effects have been discussed. An arguable role in autophagy or apoptosis control has been suggested for VD through calcium signaling at the mitochondrial and ER levels. 1,25(OH)2D3 is also an immunomodulator that affects the development of B-cells, T-cells, and NK cells in both innate and acquired immunity. The production of some anti-microbial molecules such as defensins and cathelicidins is also stimulated by VD. The overexpression of glutathione, glutathione peroxidase, and superoxide dismutase, and down-regulation of NADPH oxidase are induced by VD to reduce the oxidative stress. Moreover, the multi-organ failure due to a cytokine storm induced by SARS-CoV2 in COVID-19 may be prevented by the immunomodulatory effects of VD. It can also downregulate the renin-angiotensin system which has a protective role against cardiovascular complications induced by COVID-19. Given the many experimental and molecular evidences due to the potential protective effects of VD on the prevention of the COVID-19-induced morbidities, a VD supplementation is suggested to prevent the lethal side-effects of the infection. It is particularly recommended in VD-deficient patients or those at greater risk of serious or critical effects of COVID-19, including the elderly, and patients with pre-existing chronic diseases, especially those in nursing homes, care facilities, and hospitals.

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