metformin

Overview

Metformin is a first-line oral antidiabetic drug in the biguanide class and one of the most widely prescribed agents for type 2 diabetes mellitus. It is valued for lowering blood glucose without directly stimulating insulin secretion, and it is commonly used as a foundational therapy in combination regimens with agents such as empagliflozin, semaglutide, and other glucose-lowering drugs. In recent biomedical literature, metformin is also frequently discussed as a repurposed or adjunctive agent in cancer, neurodegeneration, inflammatory disease, and tissue repair.

Mechanistically, metformin is commonly described as an inhibitor of mitochondrial electron transport chain complex I, with downstream effects on cellular energy sensing and metabolism, including AMPK-related signaling. Recent studies also connect metformin with modulation of pathways such as PI3K/AKT/mTOR, JAK2/STAT3, Tlr2/Tlr4 signaling, and CaMKKβ/AMPK signaling, as well as effects on autophagy, ferroptosis, oxidative stress, and inflammatory polarization. Beyond its therapeutic use, metformin has also attracted attention because of formulation issues, including nitrosamine impurity concerns in some tablet products.

Focus of Latest Publications

Recent publications have continued to examine metformin as a repurposed therapy across cancer, metabolic disease, and tissue repair. In oncology, studies evaluated metformin alone or in combination with other agents, including ivermectin in MCF-7 breast cancer cells, losartan and rosiglitazone in triple-negative breast cancer cells, and methylene blue-mediated photodynamic therapy in oral squamous cell carcinoma. Additional work identified metformin as a putative lead against EGFR in drug-repurposing screening, linked its anticancer activity in hepatocellular carcinoma to reduced METTL3-mediated m6A methylation, and reported that metformin can induce PARP1-mediated cell death in nasopharyngeal carcinoma cells. Mechanistic studies also implicated metformin in suppressing PD-L1 expression through the SLC5A11-AMPK-IRF1 axis and in disrupting ATP5I-associated F1F0-ATP synthase oligomerization, supporting its continued investigation as an anticancer and immunomodulatory agent.

Several studies focused on metformin in regenerative medicine and inflammatory disease models. Metformin was incorporated into biomaterials for localized delivery, including PEG hydrogels for diabetic foot ulcers, ROS-responsive double-network hydrogels for periodontitis, intestinal-targeted phytoglycogen carriers, and biomimetic or antiswelling hydrogels for brain injury repair. These systems generally aimed to combine sustained metformin release with microenvironmental modulation, and the reported findings included reduced inflammation, altered macrophage polarization, improved oxidative stress handling, enhanced osteogenesis or neurogenesis, and accelerated wound or tissue repair. Related studies also described metformin-containing microneedle patches and cerium-metformin complexes for periodontal bone regeneration, as well as metformin-loaded liposomes targeting leptin receptor-positive endometriotic lesions, where the formulation outperformed free metformin and was reported to induce autophagy-mediated degradation of estrogen receptor β.

Beyond cancer and biomaterials, metformin was studied in models of aging, neurodegeneration, and metabolic dysfunction. In animal studies, metformin attenuated age-related bone loss when combined with taurine, reduced ciliary muscle aging by downregulating GSK-3β, and partially lessened autism-related behaviors in maternally separated mice by reducing hippocampal oxidative stress and inflammatory cytokine expression. In an intracerebroventricular streptozotocin rat model of Alzheimer’s disease, metformin improved antioxidant and anti-inflammatory markers, while a separate report described metformin-associated encephalopathy in a dialysis patient and another highlighted metformin-associated functional vitamin B12 deficiency presenting as subacute combined degeneration. Metformin was also examined as an add-on to antidiabetic regimens, including HTD1801, anagliptin, empagliflozin, and dorzolamide, and in real-world studies it remained the most frequently prescribed glucose-lowering agent in Hispanic adults with type 2 diabetes and was commonly used to manage alpelisib-induced hyperglycemia.

Other recent publications addressed metformin’s broader pharmacology and translational context. A mechanistic study identified ATP5I as a target mediating metformin’s metabolic and antiproliferative effects, while another showed that metformin can induce DDIT4 and silence HIV in vitro. Observational work in geriatric rehabilitation inpatients associated metformin use with lower 1-year mortality, and a randomized pharmacokinetic study confirmed bioequivalence of a metformin/pioglitazone tablet under fasting and fed conditions. Metformin also appeared in environmental monitoring of wastewater, where it was among the most frequently detected pharmaceuticals, underscoring its widespread use and persistence in the environment.

Key Publications

• NEWJun Combined metformin and Taurine attenuate age-related bone loss. (Molecular biology reports, 2026, PMID 42364025): "This study aimed to investigate whether combined Metformin and Taurine (Met + Ta) treatment could attenuate aging-associated skeletal deterioration and preserve BMSC function."
• NEWJun Investigation of metformin analogues in targeting signaling molecules of head and neck cancer pathways by computational approaches. (Scientific reports, 2026, PMID 42331865): "In response to this critical issue, this study seeks to evaluate the efficacy of the FDA-approved drug metformin as an anti-cancer agent."
• NEWJun Metformin enhances methylene blue-mediated photodynamic therapy in oral squamous cell carcinoma. (Journal of the Egyptian National Cancer Institute, 2026, PMID 42324424): "Considering metformin's potential to reduce cancer risk and inhibit proliferation, therefore the present study aims to evaluate its ability to potentiate the methylene blue-mediated photodynamic effect against the growth of tongue cancer cells in vitro and the possible molecular mechanisms of action involved."
• NEWJun An MFO@BCZT- and metformin-integrated biomimetic hydrogel for magnetoelectric stimulation-induced neurogenesis and neuroprotection, synergistically promoting brain tissue repair. (Journal of materials chemistry. B, 2026, PMID 42300462): "We confirmed that the metformin in the hydrogel effectively inhibited lipopolysaccharide (LPS)-induced M1 polarization of BV2 microglia, providing neuroprotection."
• NEWJun A case of metformin-associated encephalopathy in a patient undergoing maintenance hemodialysis. (CEN case reports, 2026, PMID 42289604): "Metformin is a major drug for the treatment of type 2 diabetes mellitus; however, its use is not recommended in dialysis patients due to the risk of lactic acidosis."
• NEWJun HTD1801 in Combination with Metformin for Type 2 Diabetes. (NEJM evidence, 2026, PMID 42251702): "The safety and efficacy of HTD1801 as an add-on to metformin among patients with T2D with inadequate glycemic control despite stable metformin use have not been well evaluated."
• Jun Metformin Partially Lessens Autism-Related Behaviors in Mice Subjected to Maternal Separation Stress by Combating Hippocampal Neuroinflammation and Oxidative Stress Imbalance. (Journal of biochemical and molecular toxicology, 2026, PMID 42224401): "In conclusion, metformin appears to alleviate autism-related behaviors in MS mice..."
• Jun An Integrated Pharmacological Evaluation and GC-MS/MS-Guided Metabolite Profiling of Diospyros sylvatica Roxb. Leaves Revealing Analgesic, Antioxidant, and Antidiabetic Activities. (Chemistry & biodiversity, 2026, PMID 42218796): "At 400 mg/kg, chloroform and ethyl acetate fractions significantly reduced blood glucose by 50.14% and 36.60% at 180 min compared with metformin (64.02%)."
• May An antiswelling biodegradable hydrogel reshapes electro-microenvironment to drive endogenous neuroregeneration after brain defect. (Science advances, 2026, PMID 42213827): "Herein, we design an antiswelling, biodegradable adhesive hydrogel through supramolecular self-assembly of two Food and Drug Administration-approved drugs (lipoic acid and metformin) via multi-hydrogen bonding with precise regulation of solution pH."
• May Development of metformin-encapsulated poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles. (Molecular biology reports, 2026, PMID 42207379): "In this study, we investigated the effects of free metformin, a PLGA-PEG copolymer, and PLGA-PEG-MET nanoparticles on FTC-133 thyroid cancer cells."