Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1

Maurmann et al., bioRxiv, doi:10.1101/2025.09.12.675877, Sep 2025

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Metformin for COVID-19

3rd treatment shown to reduce risk in July 2020, now with p < 0.00000000001 from 107 studies.

Lower risk for mortality, ventilation, ICU, hospitalization, progression, and recovery.

No treatment is 100% effective. Protocols combine treatments.

6,100+ studies for 180 treatments. c19early.org

In vitro study showing that metformin suppresses inflammatory responses in human monocytes exposed to SARS-CoV-2 spike protein subunit 1.

17 preclinical studies support the efficacy of metformin for COVID-19:

4 in silico studies1-4

9 in vitro studies2,5-12

4 in vivo animal studies7,8,10,13

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)14. Metformin inhibits SARS-CoV-2 in vitro11,12, minimizes LPS-induced cytokine storm in a mouse model13, 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 activation15, 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 reduce COVID-19 severity and long COVID by inhibiting NETosis via suppression of protein kinase C activation16, 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 storm17, 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, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity18.

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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.mdpi.com, doi.org.

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.nature.com, doi.org.

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.scienceopen.com, doi.org.

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.springer.com, doi.org.

5. Maurmann et al., Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1, bioRxiv, doi:10.1101/2025.09.12.675877.biorxiv.org, doi.org.

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.wiley.com, doi.org.

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.wiley.com, doi.org.

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.mdpi.com, doi.org.

9. Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.sciencedirect.com, doi.org.

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.sciencedirect.com, doi.org.

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.sciencedirect.com, doi.org.

12. Parthasarathy et al., Metformin Suppresses SARS-CoV-2 in Cell Culture, bioRxiv, doi:10.1101/2021.11.18.469078.biorxiv.org, doi.org.

13. 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.spandidos-publications.com, doi.org.

14. 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.frontiersin.org, doi.org.

15. 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.mdpi.com, doi.org.

16. 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.sciencedirect.com, doi.org.

17. 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.biorxiv.org, doi.org.

18. Petakh et al., Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes, Viruses, doi:10.3390/v16020281.mdpi.com, doi.org.

Maurmann et al., 12 Sep 2025, USA, preprint, 5 authors. Contact: bdpence@memphis.edu.

In vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Metformin All

Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1

Rafael Moura Maurmann, Kierstin Davis, Negin Mosalmanzadeh, Brenda Landvoigt Schmitt, Brandt D Pence

doi:10.1101/2025.09.12.675877

Background: Severe COVID-19 is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin's main interactions and their respective isolated effects in modulating monocyte inflammatory response to SARS-CoV-2 stimulation. Methods : Classical human monocytes were isolated from healthy 18-40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis, and inflammatory gene expression by qPCR. Stimulated monocytes were either pre-treated with metformin, rotenone, S1QEL, or A769662. Results: Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pre-treatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither complex I specific ROS scavenging. Conversely, A769662 induced AMPK activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin's mode of action upon S1 stimulation. Conclusions: In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin's anti-inflammatory effect.

Author Contributions BP conceived the study. BP designed experiments. RMM, KD, NM, BLS, and BP collected data. RMM and BP analyzed data. RMM prepared the first manuscript draft. BP edited the manuscript draft. All authors read and approved the final manuscript.

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DOI record: { "DOI": "10.1101/2025.09.12.675877", "URL": "http://dx.doi.org/10.1101/2025.09.12.675877", "abstract": "Abstract\n \n Background\n Severe COVID-19 is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin’s main interactions and their respective isolated effects in modulating monocyte inflammatory response to SARS-CoV-2 stimulation.\n \n \n Methods\n Classical human monocytes were isolated from healthy 18-40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis, and inflammatory gene expression by qPCR. Stimulated monocytes were either pre-treated with metformin, rotenone, S1QEL, or A769662.\n \n \n Results\n Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pre-treatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither complex I specific ROS scavenging. Conversely, A769662 induced AMPK activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin’s mode of action upon S1 stimulation.\n \n \n Conclusions\n In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin’s anti-inflammatory effect.\n ", "accepted": { "date-parts": [ [ 2025, 9, 12 ] ] }, "author": [ { "ORCID": "https://orcid.org/0000-0003-1759-1778", "affiliation": [], "authenticated-orcid": false, "family": "Maurmann", "given": "Rafael Moura", "sequence": "first" }, { "affiliation": [], "family": "Davis", "given": "Kierstin", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-7518-8066", "affiliation": [], "authenticated-orcid": false, "family": "Mosalmanzadeh", "given": "Negin", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5823-2611", "affiliation": [], "authenticated-orcid": false, "family": "Schmitt", "given": "Brenda Landvoigt", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4059-9092", "affiliation": [], "authenticated-orcid": false, "family": "Pence", "given": "Brandt D.", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 9, 13 ] ], "date-time": "2025-09-13T03:55:13Z", "timestamp": 1757735713000 }, "deposited": { "date-parts": [ [ 2025, 9, 16 ] ], "date-time": "2025-09-16T18:35:19Z", "timestamp": 1758047719000 }, "funder": [ { "name": "University of Memphis / University of Tennessee Health Science Center CORNET" }, { "DOI": "10.13039/100000968", "award": [ "18AIREA33961089" ], "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/100000968", "id-type": "DOI" } ], "name": "American Heart Association" }, { "DOI": "10.13039/100000968", "award": [ "19TPA34910232" ], "doi-asserted-by": "crossref", "id": [ { "asserted-by": "crossref", "id": "10.13039/100000968", "id-type": "DOI" } ], "name": "American Heart Association" }, { "name": "University of Memphis College of Health Sciences" } ], "group-title": "Immunology", "indexed": { "date-parts": [ [ 2025, 9, 18 ] ], "date-time": "2025-09-18T16:21:41Z", "timestamp": 1758212501246, "version": "3.44.0" }, "institution": [ { "name": "bioRxiv" } ], "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2025, 9, 12 ] ] }, "license": [ { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 9, 12 ] ], "date-time": "2025-09-12T00:00:00Z", "timestamp": 1757635200000 } } ], "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2025.09.12.675877", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2025, 9, 12 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2025, 9, 12 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2025091611351074000_2025.09.12.675877v1.1", "unstructured": "World Health Organization. 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