Loss of prolyl hydroxylase 2 (PHD2) activates hypoxia-inducible factor (HIF)-dependent hypoxic response including enhanced anaerobic glycolysis, which releases great amount of lactate from cells into circulation. However, surprisingly, systemic activation of hypoxic response by PHD2 inhibition in mice did not lead to hyperlactatemia. This serendipitous phenomenon led us to hypothesize that the activated hypoxic response enhances Cori cycle, the lactate-glucose carbon recycling system between muscle and liver, and then reduces circulating lactate level. Here we show that liver-specific inactivation of PHD2 improves the survival of lactic acidosis by activating Cori cycle in the liver, and pharmaceutical inhibition of PHDs also improves the survival of lethal lactic acidosis induced by endotoxin shock. Lactic acidosis is also known to be induced by metformin, which is a popular therapeutic for type 2 diabetes mellitus and also has anti-cancer and anti-aging properties but is contraindicated in individuals with chronic kidney disease (CKD) due to the risk of metformin-associated lactic acidosis (MALA). We also report that treatment with a PHD-inhibitor per os significantly improves the survival rate of MALA in CKD mice. Our findings would provide a new concept that the oxygen sensor PHDs serve as new therapeutic targets for the treatment of endotoxin shock-induced lactic acidosis or MALA. The application of PHD-inhibitor as the rescue agent for the renal anemia or myocardial infarction will be also discussed.