Wu X, et al. - In head and neck squamous cell carcinoma (HNSCC), whether aberrant cell growth is inhibited by metformin via its direct action on HNSCC cells, was investigated in this study. Researchers engineered representative HPV- and HPV+ HNSCC cells harboring typical genetic alternations to express the yeast mitochondrial NADH dehydrogenase (NDI1) protein (which is insensitive to metformin). This was done to determine the tumor cell autonomous impacts of metformin. The inhibitory impacts of metformin on mitochondrial complex I were rescued by NDI1 expression. In addition, the ability of metformin to stimulate AMPK and inhibit mTOR signaling both in vitro and in vivo was abolished by NDI1 expression. NDI1 expression was found sufficient to render metformin ineffective to prevent HNSCC tumor growth. The possibility of a direct action of metformin on cancer initiating cells leading to the prevention of their progression to HNSCC, is supported in this study. In future early-stage clinical trials, this could inform the selection of patients at risk of developing HNSCC.