2-deoxy-d-glucose + metformin

2-deoxy-d-glucose + metformin is a combination of two small molecule drugs—2-deoxy-d-glucose (2DG), a glycolysis inhibitor and glucose analog, and metformin, a biguanide antidiabetic medication with known effects on mitochondrial function. This combination has been extensively studied in preclinical cancer models, particularly for synergistic cytostatic and cytotoxic effects. Mechanistically, 2DG inhibits glycolysis, reducing cellular ATP production, while metformin inhibits mitochondrial complex I, further restricting ATP generation and activating AMP-activated protein kinase (AMPK). Together, the two agents induce strong metabolic stress, leading to suppressed proliferation, apoptosis, mitochondrial stress, and altered PD-L1 expression. This combination is under preclinical and proof-of-concept clinical evaluation, most notably for cancer and polycystic kidney disease, but is not an approved commercial product[1][2][3][4][5][6][7].