Metformin in Antiviral Therapy: Evidence and Perspectives

1. Introduction

Metformin, a first-line medication primarily prescribed for type 2 diabetes (T2DM), has garnered attention far beyond its glucose-lowering effects, showing remarkable potential in modulating host responses to viral and bacterial pathogens [1,2,3]. Initially celebrated for its ability to enhance insulin sensitivity and activate AMP-activated protein kinase (AMPK), metformin has demonstrated a breadth of influence on cellular metabolism, immune modulation, and oxidative stress—all mechanisms that extend its effects into the realm of infectious disease control [4,5,6]. As such, metformin’s influence on cellular processes has positioned it as a promising agent for enhancing host defenses against a range of viral infections and bacterial pathogens [7,8,9]. Some studies indicate metformin's potential in enhancing therapeutic outcomes, with its effectiveness demonstrated in bacterial and cancer cell activity [2,10,11,12]. Metformin demonstrates pleiotropic benefits, contributing to the improvement of multiple conditions, including thyroid-related disorders and other diseases [13,14,15,16,17]. Metformin is associated with minimal side effects compared to other medications, with the most common being gastrointestinal disturbances, which are generally mild and transient [18,19,20,21,22].

In the context of viral infections, metformin has shown the potential to interfere with viral replication and spread by creating an intracellular environment that is less conducive to viral survival [23,24] (Figure 1). One of the primary mechanisms underlying this antiviral effect is metformin's activation of AMPK, which shifts host cellular metabolism away from the high-energy states that many viruses exploit for their replication cycles [25,26]. Additionally, metformin enhances the production of interferons and other cytokines, such as interleukin-6 (IL-6] and tumor necrosis factor-alpha (TNF-α), which play essential roles in the innate immune response to viral infection and chronic diseases [27,28,29]. Through these pathways, metformin can help mount a more robust immune response, contributing to the containment of various viruses, including influenza, SARS-CoV-2 and cytomegalovirus [30,31,32].

Metformin’s modulation of inflammatory responses provides a dual benefit by enhancing immune cell recruitment to infection sites while preventing excessive inflammation that can cause tissue damage [27,33,34,35]. This balanced immune response can improve outcomes, especially in chronic infections or viral infections that might lead to significant tissue damage [36,37,38,39]. These combined mechanisms suggest that metformin’s effects extend beyond glucose regulation, impacting pathways critical for antiviral defenses [40,41,42,43].

2. Metformin in Viral Infections and Its Therapeutic Applications Across Multiple Pathogens

2.1. Metformin's Antiviral Potential Against Influenza: Mechanisms and Therapeutic Insight

Influenza viruses, precisely the types A and B, are segmented RNA viruses belonging to the Orthomyxoviridae family, which utilize host cell machinery to replicate and undergo frequent antigenic variation, contributing to seasonal epidemics and occasional pandemics [44,45]. Metformin has garnered significant attention for its potential antiviral effects, particularly against the influenza virus [46,47] (Table 1). Emerging research has highlighted the drug's ability to modulate host cellular pathways, inhibiting viral replication [48,49]. The primary mechanism of metformin’s antiviral action involves the activation of AMPK, a central regulator of cellular energy homeostasis [50,51]. By activating AMPK, metformin disrupts metabolic processes essential for viral replication, thereby hindering the influenza virus's ability to use host resources efficiently [32,52]. This metabolic interference results in a cellular environment less conducive to viral propagation [48,53].

In addition to altering metabolic pathways, metformin exerts significant immunomodulatory effects [54,55]. The activation of AMPK leads to the downregulation of pro-inflammatory cytokines, such as IL-6 and tumor necrosis TNF-α, which are typically elevated during influenza infections and contribute to severe inflammatory responses [56,57,58]. Metformin may help mitigate hyperinflammation-related complications, such as acute respiratory distress syndrome (ARDS), by tempering the inflammatory cascade [59,60]. Furthermore, metformin appears to influence the innate immune response by enhancing the efficiency of autophagy, a process critical for the clearance of viral particles and damaged cellular components [61,62]. Enhanced autophagy facilitates viral elimination and preserves cellular integrity during infection [63,64].

Experimental evidence from in vitro studies has shown that metformin treatment significantly reduces viral loads within infected cell cultures [65,66]. This observation suggests a potential direct impact on virus-host interactions, possibly through the inhibition of viral entry or the disruption of viral genome replication [67,68]. Animal models infected with the influenza virus have also demonstrated the protective effects of metformin, with treated subjects displaying lower viral titers, reduced lung inflammation, and improved survival outcomes compared to untreated controls [69,70]. The immunomodulatory role of metformin may be particularly beneficial in moderating the host's inflammatory response, thus preventing tissue damage caused by excessive immune activation [40,71].

Metformin influences the expression of several key genes involved in the antiviral response to influenza. It activates the AMPK gene, which plays a central role in cellular energy regulation and restricts viral replication by reducing available energy sources [72,73]. Metformin also upregulates interferon-beta 1 (IFNB1], which enhances the antiviral immune response by promoting interferon production [74]. The drug further stimulates microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 (BECN1) genes, essential for autophagy processes that help degrade intracellular influenza particles [75]. Metformin modulates superoxide dismutase 2 (SOD2), increasing reactive oxygen species that can directly damage viral structures [76,77,78].

Moreover, metformin has been reported to improve the efficacy of conventional antiviral treatments when administered concurrently [79,80,81]. This synergistic effect may be due to its ability to enhance the overall antiviral response while reducing inflammation [82,83,84]. Some observational studies in humans have indicated that individuals with T2DM who are on metformin therapy tend to experience less severe influenza symptoms and lower hospitalization rates compared to those not receiving the medication [32,85]. Despite these promising findings, the exact molecular mechanisms underlying metformin’s antiviral effects remain a subject of ongoing research [86,87]. The potential roles of AMPK-mediated inhibition of mTOR signaling pathways, modulation of cellular redox status, and alteration of lipid metabolism are areas of particular interest [88,89].

Additionally, metformin may indirectly affect viral replication through its influence on mitochondrial function and the reduction of oxidative stress, further contributing to an inhospitable environment for the virus [90]. The drug’s capacity to improve mitochondrial biogenesis and reduce reactive oxygen species (ROS) production has implications for cellular health and viral control [91,92]. Understanding the multifaceted impact of metformin on cellular and viral processes could provide insights into novel therapeutic approaches [40,93]. Thus, while the evidence supports metformin’s potential as a complementary antiviral agent, comprehensive clinical trials are required to establish its efficacy and safety for widespread use in treating influenza infections, particularly in vulnerable and immunocompromised populations [32,94].

2.2. Metformin in the Context of COVID-19: Mechanisms of Action and Its Potential as a Therapeutic Agent Against SARS-CoV-2

SARS-CoV-2, the causative agent of the COVID-19 pandemic, has prompted extensive research into potential therapeutic agents, including metformin, which may modulate host immune responses and alter the disease trajectory through various cellular mechanisms [95,96,97,98,99]. Metformin has attracted attention for its potential impact on SARS-CoV-2 infection and the progression of COVID-19 [40,100,101] (Table 2). The drug’s anti-inflammatory and immunomodulatory effects are particularly relevant, given the role of excessive inflammation, or cytokine storm, in severe cases of COVID-19 and chronic diseases [102,103,104]. A central mechanism through which metformin may exert its protective influence is the activation of AMPK, which is linked to the inhibition of the mTOR pathway [105,106]. This pathway is involved in immune cell activation and inflammatory responses, and its modulation by metformin could help dampen hyperinflammation and promote more balanced immune regulation during SARS-CoV-2 infection [95,107,108].

Metformin also reduces oxidative stress, which is significantly elevated in severe COVID-19 cases [109,110]. By decreasing the production of ROS and enhancing mitochondrial function, metformin may mitigate cellular damage caused by viral infection and excessive inflammation [111,112]. Observational studies have indicated that diabetic patients using metformin prior to contracting SARS-CoV-2 have a lower risk of severe complications and mortality compared to those not on metformin therapy [113,114,115,116]. Nevertheless, these results are preliminary, and some studies, including those examining hematological markers, are necessary to establish a definitive causal relationship [117,118,119].

Metformin’s effects on the renin-angiotensin-aldosterone system (RAAS) have also been considered necessary, as SARS-CoV-2 utilizes the angioten-sin-converting enzyme 2 (ACE2] receptor for cell entry [120,121,122]. Although the exact relationship between metformin and ACE2 expression is not fully understood, it has been hypothesized that the drug might modulate ACE2 levels, potentially affecting viral entry or disease severity [24,120,123,124]. Moreover, metformin improves endothelial function, which may offer protection against vascular complications commonly observed in COVID-19, such as endothelial damage, elevated blood pressure and thrombosis [41,125,126,127,128,129].

The influence of metformin on gut microbiota is another area of interest, given the role of gut health in immune function and systemic inflammation [130,131,132,133,134,135]. Metformin could potentially reduce systemic inflammation and enhance immune resilience by altering microbial composition and promoting gut barrier integrity [23,119,136,137]. Preliminary in studies suggest that metformin and other medications might also inhibit viral replication, though the direct anti-viral activity against SARS-CoV-2 remains to be validated [26,138,139,140,141,142,143].

Another mechanism through which metformin may benefit COVID-19 patients is by improving glucose metabolism and reducing insulin resistance [144,145,146]. Since hyperglycemia and insulin resistance are associated with poorer outcomes in COVID-19, metformin’s glucose-lowering properties could play a role in better disease management [147,148]. The idea of re-purposing metformin as an adjunctive treatment for COVID-19 is under active investigation, especially for high-risk groups, such as individuals with diabetes or obesity [115].

2.3. Metformin and HIV: Exploring Its Potential in Modulating Immune Responses and Enhancing Treatment Outcomes

Human Immunodeficiency Virus (HIV), a virus that causes chronic immune system dysfunction, remains a significant global health challenge, and recent research has explored the potential benefits of repurposing existing medications, such as metformin, to improve outcomes in people living with HIV [87,154,155]. Metformin has shown promise in modulating immune responses and could influence the course of HIV infection [154,156] (Table 3). Emerging evidence suggests that metformin may have immunoregulatory and anti-inflammatory properties relevant to HIV-induced chronic immune activation [154,157]. One of the critical mechanisms by which metformin exerts its effects is activating AMPK, a crucial regulator of cellular metabolism. AMPK activation by metformin has been associated with inhibiting the mTOR signaling pathway, which is involved in T cell activation and proliferation [158,159]. By modulating these pathways, metformin may help to reduce the hyperactivation of immune cells that is characteristic of chronic HIV infection [160,161].

Furthermore, metformin has been observed to influence the function of regulatory T cells (Tregs), which play a vital role in maintaining immune homeostasis [162,163]. Enhancing Treg activity could potentially mitigate the immune dysregulation seen in people living with HIV [164,165]. Studies have also indicated that metformin may decrease systemic inflammation, as evidenced by reduced levels of inflammatory markers such as IL-6 and C-reactive protein (CRP) [166,167]. This reduction in inflammation may be beneficial in managing HIV-associated comorbidities, such as cardiovascular disease and metabolic syndrome, which are exacerbated by chronic inflammation [168,169].

Metformin’s impact on gut microbiota has garnered interest, as dysbiosis is a known factor in the immune dysfunction observed in HIV [170,171,172]. By improving gut barrier integrity and altering microbial composition, metformin may help reduce microbial translocation, a driver of systemic inflammation in HIV [173,174,175,176]. Studies have shown that metformin can reduce HIV replication in specific cell models, although the clinical significance of this finding remains unclear [177,178,179]. The potential of metformin to complement antiretroviral therapy (ART) is an area of ongoing research, as it may enhance immune recovery and reduce residual inflammation despite effective viral suppression [87,154].

Observational data have indicated that people with HIV who use metformin for diabetes management may experience slower progression of HIV-associated complications [180,181]. Nonetheless, despite the substantial body of research in this field, randomized clinical trials are required to validate these effects and to establish the optimal dosing and safety profile in the context of HIV [182,183,184]. The immunometabolic effects of metformin make it a candidate for further exploration as part of a comprehensive strategy to address the long-term health challenges faced by people living with HIV [185,186].

2.4. Metformin in Hepatitis C: Potential Therapeutic Effects on Viral Replication, Inflammation, and Hepatic Fibrosis

Hepatitis C virus (HCV), a hepatotropic, single-stranded RNA virus of the Flaviviridae family, is a primary global health concern due to its ability to cause chronic liver disease, leading to cirrhosis, hepatocellular carcinoma (HCC), and increased mortality rates, particularly in individuals with comorbid conditions such as insulin resistance, metabolic syndrome, and HIV coinfection [193,194,195]. Metformin has gained attention for its potential impact on the pathogenesis of chronic HCV infection, offering a promising adjunctive approach to managing this viral disease (Table 4). HCV infection is characterized by persistent liver inflammation, immune dysregulation, and the progressive development of fibrosis, which can eventually lead to cirrhosis and HCC [196,197]. The potential benefits of metformin in HCV infection are thought to stem from its ability to modulate several key cellular pathways involved in viral replication, inflammation, and hepatic fibrosis [198,199]. One of the primary mechanisms by which metformin exerts its effects is activating AMPK, a crucial regulator of cellular energy homeostasis [159,200].

AMPK is activated by metformin and inhibits the mTOR signaling pathway, a critical regulator of cell growth, protein synthesis, and immune cell activation [158,201]. This inhibition of mTOR may attenuate the inflammatory response central to the chronic liver injury observed in HCV infection [202,203]. In addition to its effects on mTOR, AMPK activation by metformin has been shown to reduce oxidative stress, a hallmark of HCV-induced liver damage [204,205]. ROS, produced during viral replication and inflammation, contribute to hepatocellular injury, fibrosis, and liver disease progression [206,207]. By reducing ROS production, metformin may help protect against cellular damage and limit the advancement of fibrosis [208,209].

Moreover, metformin’s ability to enhance insulin sensitivity and reduce hyperglycemia is particularly relevant in HCV patients who exhibit insulin resistance [210,211]. This condition exacerbates liver damage and accelerates disease progression. Insulin resistance in the context of HCV infection is associated with an increased risk of steatosis, advanced fibrosis, and poor treatment outcomes [212,213]. By improving insulin sensitivity, metformin may help mitigate these metabolic disturbances and thereby slow the progression of liver disease [214]. Additionally, metformin has been reported to exert an anti-inflammatory effect by decreasing the levels of pro-inflammatory cytokines such as IL-6 and TNF-α, which are elevated in chronic HCV infection and contribute to hepatic inflammation and fibrosis [30,215].

The interplay between metformin and immune modulation in HCV infection is also interesting [211,216]. Metformin may influence the function of innate immune cells, such as macrophages and dendritic cells, by reducing their activation and promoting a more balanced immune response [34,217]. This modulation of the immune system could help reduce the chronic inflammation and immune-mediated liver damage characteristic of HCV infection [218]. Additionally, metformin has been shown to inhibit the activation of hepatic stellate cells (HSCs), which play a crucial role in developing liver fibrosis [219,220]. By inhibiting HSCs activation and collagen deposition, metformin may help prevent or slow the progression of fibrosis in HCV-infected individuals [221].

Studies have suggested that metformin may also directly impact HCV replication [222]. While the exact mechanisms are not fully understood, some evidence points to the potential viral entry or replication inhibition within hepatocytes [223]. The potential for metformin to complement antiviral therapies in HCV infection is an area of ongoing research, particularly in individuals with comorbidities such as diabetes or metabolic syndrome [224,225]. Given that insulin resistance is a known risk factor for HCV-related liver disease, metformin’s effects on glucose metabolism and its potential to improve hepatic lipid metabolism are additional benefits in this context [226].

Furthermore, metformin’s effects on the gut microbiota have gained attention in the context of liver disease [227,228]. Dysbiosis, or an imbalance in the gut microbiome, has been implicated in the pathogenesis of liver diseases, including HCV infection [229,230]. Metformin has been shown to modulate gut microbiota composition, which could lead to reduced intestinal permeability and decreased microbial translocation, thereby lowering systemic inflammation and its impact on the liver [231,232]. By improving gut barrier function, metformin may reduce the chronic low-grade inflammation observed in HCV patients [233,234].

While the available preclinical data support metformin’s potential as a therapeutic adjunct in HCV infection, clinical evidence remains limited, and more randomized controlled trials are needed to understand its efficacy and safety profile in this context fully [11,196,235]. Combining metformin with direct-acting antiviral agents (DAAs) for HCV may represent an innovative therapeutic strategy, potentially enhancing viral eradication and improving liver function [236,237]. Metformin shows potential in modulating antiviral therapy for hepatitis C, especially when combined with sofosbuvir, velpatasvir, and ledipasvir [198,238]. Co-administration of metformin with DAAs like ledipasvir and sofosbuvir may offer a pathophysiological advantage in managing patients with hepatitis C and concurrent metabolic disorders [236,239]. However, the effects of metformin on HCV treatment outcomes are yet to be conclusively demonstrated in clinical trials [240,241].

2.5. Metformin in Hepatitis B: Targeting Insulin Resistance, Inflammation, and Fibrosis in Chronic Liver Disease

Hepatitis B virus (HBV) is a major global health threat, with chronic infection potentially leading to cirrhosis, HCC, and significant morbidity and mortality [251]. While antiviral therapies, such as nucleos(t)ide analogs, are widely used to suppress HBV replication, there is growing interest in repurposing existing medications to improve treatment outcomes and address co-morbidities associated with HBV infection [252]. Metformin has garnered attention due to its pleiotropic effects and potential impact on HBV pathogenesis [13,253] (Table 4). Chronic HBV infection is often associated with dysregulated immune responses, inflammation, and liver damage, and metformin may influence several key processes that contribute to these disease mechanisms [254,255].

Insulin resistance, a common comorbidity in HBV patients, particularly in those with metabolic syndrome or non-alcoholic fatty liver disease (NAFLD), is known to exacerbate liver damage and increase the risk of fibrosis [256,257]. Metformin’s ability to improve insulin sensitivity and reduce hyperglycemia is particularly relevant in HBV-infected individuals, as insulin resistance is associated with worse outcomes in chronic liver disease [258,259]. Metformin may reduce the risk of steatosis, hepatic inflammation, and fibrosis progression in patients with HBV infection by improving glucose metabolism [221,260]. Moreover, metformin may influence immune modulation in HBV infection by affecting the function of innate and adaptive immune cells [253]. Metformin has been demonstrated to regulate macrophage activation, promoting an anti-inflammatory phenotype, which could help reduce the chronic inflammation observed in HBV-related liver disease [261,262]. The modulation of T cell responses is also interesting, as HBV infection often leads to a dysregulated immune response characterized by persistent viral replication and immune exhaustion [263,264]. Metformin may promote a more balanced immune response by modulating the immune system, which could contribute to viral control and limit hepatic damage [32,265].

The potential role of metformin in mitigating HBV-related liver fibrosis is particularly compelling. HSCs, which are responsible for producing extracellular matrix proteins and fibrosis, are activated in response to chronic inflammation and viral replication [266,267]. Studies have shown that metformin can inhibit the activation of HSCs, thereby reducing collagen deposition and fibrosis progression [268]. By targeting this essential aspect of the fibrotic process, metformin may slow the progression to cirrhosis and hepatocellular carcinoma, the most severe outcome of chronic HBV infection [269,270].

Furthermore, metformin’s effect on gut microbiota composition may influence HBV pathogenesis, as gut dysbiosis and microbial translocation have been implicated in the progression of liver disease [271,272]. Metformin has been shown to alter the gut microbiome, potentially improving gut barrier function and reducing systemic inflammation [273,274]. This could benefit liver inflammation and fibrosis, as the gut-liver axis plays a significant role in the pathogenesis of chronic liver diseases, including HBV [275].

Clinical studies examining the effects of metformin in HBV-infected individuals are limited but suggest that metformin use may be associated with improved liver function and reduced levels of inflammatory markers [226,276]. Observational data indicate that patients with diabetes and chronic HBV who are treated with metformin may experience better liver outcomes compared to those not using the drug [277,278]. The use of metformin in HBV infection could also help manage comorbid conditions, such as diabetes and NAFLD, which are prevalent in HBV patients and complicate treatment and disease progression [279].

2.6. Metformin as an Antiviral: Potential Applications Against Cytomegalovirus, Herpes Simplex Virus, Zika Virus, Dengue Virus, Epstein-Barr Virus, Human Papillomavirus, and Others

Evidence suggests that metformin may inhibit the replication of several viruses, including cytomegalovirus (CMV), herpes simplex virus (HSV), Zika virus, dengue virus, Epstein-Barr virus (EBV), and human papillomavirus (HPV) [30,280,281] (Table 5). The mechanism of action appears to involve its ability to modulate cellular pathways that are critical for viral replication [87,282].

Studies show that metformin can reduce viral loads in CMV, a virus that causes chronic infection in immunocompromised individuals [283]. The drug downregulates the mammalian target of the mTOR pathway, which is essential for CMV’s protein synthesis and replication processes [281,284]. Metformin may limit CMV replication by inhibiting mTOR, suggesting its potential in therapeutic strategies against CMV-induced diseases [285,286]. CMV-induced "inflammaging" from immune cell senescence can be mitigated with interventions like senolytics or metformin, enhancing immune function in older adults [287]. CMV replication depends on mitochondrial function, with metformin showing promise as a repurposed antiviral due to its inhibition of viral replication [283]. Metformin restores impaired CD8⁺ T cell functionality in diabetic patients, linking metabolic improvement to enhanced viral immunity and reduced susceptibility to CMV [288].

Similarly, metformin has shown inhibitory effects on HSV replication, another virus known for establishing persistent infections. HSV relies on cellular resources to synthesize viral proteins and assemble virions [289,290]. Metformin’s activation of AMPK restricts these processes, potentially leading to reduced HSV reactivation rates in latently infected individuals [30,291]. Metformin alleviates herpetic stromal keratitis severity while preserving immune function, suggesting it as a safer alternative compared to 2-deoxy-D-glucose [292].

Regarding arboviruses such as Zika and dengue, metformin interferes with viral replication by modulating oxidative stress levels in host cells [280]. These viruses generate ROS for efficient replication [280,293]. Metformin, known for its antioxidant properties, reduces ROS production, indirectly impairing the replication efficiency of these viruses [294]. This effect on oxidative stress has made metformin a candidate for adjunctive therapy in treating Zika and dengue infections, which are often complicated by inflammation and tissue damage [295,296].

In the context of EBV, metformin may impact its latent and lytic phases [297]. EBV-associated diseases are often triggered by the virus's reactivation from latency, which requires a shift in host cellular metabolism [298,299]. Metformin’s ability to activate AMPK and inhibit mTOR has been linked to inhibiting EBV lytic reactivation, thus limiting its pathogenic potential [300,301].

Metformin may also reduce replication rates of the HPV by influencing cellular differentiation and proliferation processes, which HPV relies on to complete its life cycle [302]. By regulating these cellular pathways, metformin could impair HPV replication, thus reducing the risk of HPV-related cancers [303,304]. T-cell spatial distribution in HPV-positive tumors predicts response to immunotherapies, with metformin modulating CD8⁺ T-cell densities in treated cancers [305].

In addition to its metabolic effects, metformin exhibits immunomodulatory properties that may enhance the body’s antiviral defenses [306]. Research also indicates that metformin can inhibit adenovirus replication by reducing the expression of E1A proteins, essential for viral DNA replication and cell lysis [307,308,309]. This mechanism might particularly interest immunocompromised patients, where adenovirus infections are frequently more severe [310].

Moreover, studies have explored metformin’s role in controlling poxvirus infections, particularly vaccinia virus, where its influence on cellular autophagy appears relevant [311,312]. Metformin could impair viral assembly and release by modulating autophagy, thereby inhibiting the spread of infection [26,160].

4. Conclusions

Metformin, widely recognized for its anti-diabetic properties, demonstrates significant potential as a broad-spectrum antiviral agent due to its modulation of critical cellular pathways that impact viral replication. Beyond its effects on Influenza, HIV, SARS-CoV-2 (COVID-19), HCV, and HBV, metformin shows inhibitory effects on other viruses, including cytomegalovirus (CMV), herpes simplex virus (HSV), Zika virus, dengue virus, Epstein-Barr virus (EBV), human papillomavirus (HPV). Metformin’s activation of AMPK limits viral replication by reducing cellular energy resources, benefiting viruses like Influenza and SARS-CoV-2, and potentially mitigating cytokine storms in COVID-19. It also inhibits the mTOR pathway in HIV, reducing viral protein synthesis and chronic inflammation. For HBV and HCV, metformin disrupts viral replication and host metabolism, improving liver function and potentially lowering viral load. Metformin's activation of AMPK reduces cellular energy resources that viruses typically exploit, limiting replication for various viruses. Additionally, its inhibition of the mTOR pathway—crucial for processes like protein synthesis in CMV and reactivation in EBV—further suppresses viral activity.

Metformin’s modulation of oxidative stress and ROS levels provides an antiviral effect for arboviruses like Zika and dengue, as these viruses rely on elevated ROS for replication. Its ability to regulate cellular differentiation and immune response may also interfere with HPV’s life cycle. Collectively, these multifaceted actions highlight metformin’s potential as adjunctive therapy for a broad range of pathogens, opening promising avenues for future host-targeted treatments.