The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CLpro) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.

1st Department of Internal Medicine Faculty of Medicine Comenius University and University Hospital Bratislava Slovakia

2nd Department of Internal Medicine Faculty of Medicine Masaryk University and St Anne's University Hospital Brno Czech Republic

2nd Department of Surgery Faculty of Medicine Masaryk University and St Anne's University Hospital Brno Czech Republic

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Functional Sciences Victor Babes University of Medicine and Pharmacy Timisoara Romania; Center for Translational Research and Systems Medicine Victor Babes University of Medicine and Pharmacy Timisoara Romania

Department of Infectiology and Geographical Medicine Faculty Medicine Comenius University and University Hospital Bratislava Slovakia

Department of Leadership Faculty of Military Leadership University of Defence Brno Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Neurology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Pathology St Elizabeth Cancer Institute Hospital Bratislava Slovakia; Biomedical Research Centre Slovak Academy of Sciences Bratislava Slovakia

Department of Physiology and Biophysics Weill Cornell Medicine Qatar Education City Qatar Foundation Doha Qatar

Faculty of Engineering and Natural Sciences Sabanci University Orta Mahalle Tuzla Istanbul Turkey; Sabanci University Nanotechnology Research and Application Center Tuzla Istanbul Turkey

Faculty of Medicine University of Oviedo and Central University Hospital of Asturias Oviedo Spain

Human Anatomy Section Department of Experimental Biomedicine and Clinical Neurosciences University of Palermo and Euro Mediterranean Institute of Science and Technology Palermo Italy

Musculoskeletal Research Group and Tumor Biology Chair of Vegetative Anatomy Institute of Anatomy Faculty of Medicine Ludwig Maximilian University Munich Munich Germany

Sabanci University Nanotechnology Research and Application Center Tuzla Istanbul Turkey

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