metformin
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.