Metformin and phenformin attenuate SARS–CoV-2 spike protein S1-induced endothelial inflammation involving AMPK/NF-κB signaling in HUVECs
et al., Immunopharmacology and Immunotoxicology, doi:10.1080/08923973.2026.2671721, May 2026
Metformin for COVID-19
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.
No treatment is 100% effective.
Protocols combine treatments.
In vitro study showing inhibition of SARS-CoV-2 spike protein S1-induced endothelial inflammation with metformin and phenformin in human umbilical vein endothelial cells. Metformin counteracted S1 exposure by increasing AMPK phosphorylation and reducing NF-κB signaling and monocyte adhesion.
18 preclinical studies support the efficacy of metformin for COVID-19:
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI)15.
Metformin inhibits SARS-CoV-2 in vitro11,12, minimizes LPS-induced cytokine storm in a mouse model14, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS10, may protect against SARS-CoV-2-induced neurological disorders9, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation16, reduces UUO and FAN-induced kidney fibrosis10, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells10, may reduce inflammation, oxidative stress, and thrombosis via regulating glucose metabolism2, attenuates spike protein S1-induced inflammatory response and α-synuclein aggregation8, may protect against COVID-19 cognitive impairment by suppressing HIF-1α stabilization and reducing neurodegenerative protein aggregation13, may reduce COVID-19 severity and long COVID by inhibiting NETosis via suppression of protein kinase C activation17, enhances interferon responses and reduces SARS-CoV-2 infection and inflammation in diabetic models by suppressing HIF-1α signaling7, may improve COVID-19 outcomes by preventing VDAC1 mistargeting to the plasma membrane, reducing ATP loss, and preserving immune cell function during cytokine storm18, reduces hyperglycemia-induced hepatic ACE2/TMPRSS2 up-regulation and SARS-CoV-2 entry6, may reduce COVID-19 severity by suppressing monocyte inflammatory responses and glycolytic activation via AMPK pathway modulation5, may reduce glycolytic capacity and restrict SARS-CoV-2 replication via boosting mitochondrial OXPHOS with AMPK/PGC-1α activation19, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity20.
1.
Tavares et al., Investigation of Interactions Between the Protein MPro and the Vanadium Complex VO(metf)2∙H2O: A Computational Approach for COVID-19 Treatment, Biophysica, doi:10.3390/biophysica5010004.
2.
Hou et al., Metformin is a potential therapeutic for COVID-19/LUAD by regulating glucose metabolism, Scientific Reports, doi:10.1038/s41598-024-63081-0.
3.
Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.
4.
Lockwood, T., Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent, BioMetals, doi:10.1007/s10534-024-00590-5.
5.
Maurmann et al., Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1, Immunometabolism, doi:10.1097/in9.0000000000000078.
6.
Rao et al., Pathological Glucose Levels Enhance Entry Factor Expression and Hepatic SARS‐CoV‐2 Infection, Journal of Cellular and Molecular Medicine, doi:10.1111/jcmm.70581.
7.
Joshi et al., Severe SARS‐CoV‐2 infection in diabetes was rescued in mice supplemented with metformin and/or αKG, and patients taking metformin, via HIF1α‐IFN axis, Clinical and Translational Medicine, doi:10.1002/ctm2.70275.
8.
Chang et al., SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin, Biomedicines, doi:10.3390/biomedicines12061223.
9.
Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.
10.
Miguel et al., Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney, Redox Biology, doi:10.1016/j.redox.2023.102957.
11.
Ventura-López et al., Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223.
12.
Parthasarathy et al., Metformin Suppresses SARS-CoV-2 in Cell Culture, bioRxiv, doi:10.1101/2021.11.18.469078.
13.
Lee et al., SARS-CoV-2 spike protein causes synaptic dysfunction and p-tau and α-synuclein aggregation leading cognitive impairment: The protective role of metformin, PLOS One, doi:10.1371/journal.pone.0336015.
14.
Taher et al., Anti‑inflammatory effect of metformin against an experimental model of LPS‑induced cytokine storm, Experimental and Therapeutic Medicine, doi:10.3892/etm.2023.12114.
15.
Wang et al., Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1215307.
16.
Zhang et al., SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects, Pathogens, doi:10.3390/pathogens13010075.
17.
Monsalve et al., NETosis: A key player in autoimmunity, COVID-19, and long COVID, Journal of Translational Autoimmunity, doi:10.1016/j.jtauto.2025.100280.
18.
Sjögren et al., Shedding of mitochondrial Voltage-Dependent Anion Channel-1 (VDAC1) Reflects COVID-19 Severity and Reveals Macrophage Dysfunction, bioRxiv, doi:10.1101/2025.07.07.663218.
Yigitturk et al., 24 May 2026, peer-reviewed, 5 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
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