metformin + methotrexate

Metformin + methotrexate is a combination of two small molecule drugs, metformin and methotrexate. Metformin is a biguanide antihyperglycemic agent primarily used for glycemic control in type 2 diabetes mellitus, while methotrexate is an antimetabolite and antifolate drug widely used as an antineoplastic agent and immunosuppressant in conditions such as cancer, severe psoriasis, and rheumatoid arthritis. The combination has been studied for its potential synergistic effects in inflammatory diseases like psoriasis with metabolic syndrome and rheumatoid arthritis. Mechanistically, both drugs activate AMP-activated protein kinase (AMPK), leading to anti-inflammatory effects through inhibition of T-cell proliferation, reduction of proinflammatory cytokines (such as TNF-α and interferon-γ), suppression of keratinocyte growth via the ERK1/2 pathway, and modulation of the mTOR pathway. Preclinical studies also suggest that metformin may ameliorate methotrexate-induced hepatotoxicity[1][2][6][8].