Metformin in Antiviral Therapy: Evidence and Perspectives

Abstract

Metformin, a widely used antidiabetic medication, has emerged as a promising broad-spectrum antiviral agent due to its ability to modulate cellular pathways essential for viral replication. By activating AMPK, metformin depletes cellular energy reserves that viruses rely on, effectively limiting the replication of pathogens such as influenza, HIV, SARS-CoV-2, HBV, and HCV. Its role in inhibiting the mTOR pathway, crucial for viral protein synthesis and reactivation, is particularly significant in managing infections caused by HIV, CMV, and EBV. Furthermore, metformin reduces oxidative stress and reactive oxygen species (ROS), which are critical for replicating arboviruses such as Zika and dengue. The drug also regulates immune responses, cellular differentiation, and inflammation, disrupting the life cycle of HPV and potentially other viruses. These diverse mechanisms suppress viral replication, enhance immune system functionality, and contribute to better clinical outcomes. This multifaceted approach highlights metformin's potential as an adjunctive therapy in treating a wide range of viral infections.

Keywords: AMPK activation; broad-spectrum antiviral; inflammation; mTOR inhibition; metformin; oxidative stress; viral replication.

Figure 1

General antiviral mechanisms of metformin. This figure summarizes the general antiviral effects of metformin, which indirectly inhibit viral replication by targeting host cellular pathways. Metformin activates AMPK, reducing energy and lipid synthesis required for viral replication. It inhibits the mTOR pathway, limiting viral protein production, and disrupts lipid metabolism, impairing assembly and egress of viral particles. Metformin also downregulates host viral receptors, such as ACE2 (SARS-CoV-2), and modulates the immune response by reducing pro-inflammatory cytokines (e.g., IL-6, TNF-α) and suppressing immune activation, which decreases latent reservoirs (e.g., HIV).

Figure 2

This schematic illustrates the antiviral effects of metformin across different stages of the viral replication cycle for SARS-CoV-2, HIV, HCV, HBV, and influenza. Metformin inhibits viral entry by downregulating ACE2 receptor expression (SARS-CoV-2) and disrupting lipid rafts (influenza). It suppresses genome replication by inhibiting viral polymerase activity (influenza, HCV), cccDNA transcription (HBV), and reverse transcription through NF-κB inhibition (HIV). Metformin reduces viral protein synthesis by inhibiting the mTOR pathway, affecting multiple viruses, including SARS-CoV-2. It impairs viral assembly and maturation by disrupting lipid metabolism (HCV, HBV, influenza) and inhibits viral egress by interfering with lipid-mediated budding (influenza, HBV). Additionally, metformin modulates the immune response by reducing inflammation and cytokine levels (e.g., IL-6 and TNF-α), mitigating cytokine storms (SARS-CoV-2), and decreasing immune activation to shrink latent reservoirs (HIV). Figure was designed using BioRender.com.