Pathways	Metformin’s overlapping mechanisms of action	Theorized Covid-19 relationship
I. Viral entry and lifecycle	Activates AMPK, which can lead to conformational changes to ACE2 (39, 42, 43). inhibits mTOR reducing -viral protein complexes central to viral replication (39).	Decreased SARS-CoV-2 entry via the ACE2, and replication through Orf9c and Nsp7 (38, 39, 42, 43).
II. Immune modulation includes	Decreases IL-6, TNFα, and suppresses c-c motif chemokine ligand (34, 44–46); Inhibits TLR-7 signaling (40, 47, 48). Possibly boosts IL-10 as well (IL-10 is hard to interpret because it may be elevated in a response to reduce TNFα.) (34)	These cytokines contribute to morbidity in Covid-19 (37, 49, 50). Chen et al. found lower IL-6 with metformin use (14).
III. Neutrophil-extracellular traps	Decreases neutrophil-extracellular traps (NETs), which are released from neutrophils and contain DNA, histones, and proteins that are microbiocidal (51, 52). Neutrophil count dropped by >1,000 cells/mm (3) in 3 months of metformin (53). Patients with Covid-19 have had elevated levels of histones and DNA components from NETs (54). A byproduct of NETs may accelerate viral entry (55)	Excessive NET formation leads to cytokine storm and microthrombus (possibly independent of tissue factor), and ARDS in Covid-19 (54). Neutrophil infiltration in pulmonary capillaries have been an important feature of severe Covid disease (7, 34, 56, 57).
IV. Decreased glycemia	Phosphorylates AMPK (32), improving hepatic insulin sensitivity, gut utilization of glucose, GLP-1 secretion and favorably altering the gut microbiome (33).	Glycemia is associated with increased length of stay and mortality in patients with Covid-19 (58).
V. Mast cell stabilization	Inhibits IgE- and aryl hydrocarbon- mediated mast cell activation (59). Mast cells in female rats cause greater increase in TNFα than mast cells in male rats, which may explain a larger benefit from metformin in women than men with Covid (60).	Mast cell activation has been cited as an early indicator of inflammatory response to SARS-CoV2 and cytokine storm (61, 62).
VI. Decreased thrombosis	Decreases thrombosis in longterm follow-up, felt to be by inhibiting platelet activation factor and mtDNA release (63, 64).	Thrombosis is an important component of Covid-19 pathology (65, 66).
VII. Endothelial function	Significantly decreases HOMA-IR and non-significant decrease in tissue plasminogen activating factor 8 weeks after randomization to metformin (67).	Pulmonary vascular endothelitis has been found in lungs of patients with Covid-19 (68).
VIII. Pulmonary fibrosis	Increase resolution of fibrosis via AMPK activation of lung myofibroblasts (69) Reduced pulmonary fibrosis (through NFK, reduced TGF-beta, VEGF) (41).	Fibrosis occurs after Covid-infection, especially in patients with high IL-6 (70).
IX. Endosomal pH	Increasing pH via action on vacuolar ATPase, endosomal Na+/H+ exchangers (71)	High endosomal pH inhibits viral replication.