Metformin, an anti-diabetic drug, has been observed to prevent cancer progression in epidemiological and laboratory studies. However, the mechanism by which metformin inhibits tumor growth is not fully understood. This study investigates the role of mitochondrial complex I in the anti-tumor effects of metformin. The researchers found that metformin inhibits mitochondrial complex I activity and cellular respiration in human cancer cells, particularly in the presence of glucose. Metformin induced cell death in glucose-deprived cells but inhibited proliferation in glucose-rich conditions. Additionally, metformin reduced hypoxic activation of the hypoxia-inducible factor 1 (HIF-1). These effects were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase ND1 was overexpressed. In vivo, metformin inhibited the growth of control human cancer cells but not those expressing ND1. The study concludes that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.Metformin, an anti-diabetic drug, has been observed to prevent cancer progression in epidemiological and laboratory studies. However, the mechanism by which metformin inhibits tumor growth is not fully understood. This study investigates the role of mitochondrial complex I in the anti-tumor effects of metformin. The researchers found that metformin inhibits mitochondrial complex I activity and cellular respiration in human cancer cells, particularly in the presence of glucose. Metformin induced cell death in glucose-deprived cells but inhibited proliferation in glucose-rich conditions. Additionally, metformin reduced hypoxic activation of the hypoxia-inducible factor 1 (HIF-1). These effects were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase ND1 was overexpressed. In vivo, metformin inhibited the growth of control human cancer cells but not those expressing ND1. The study concludes that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.