Inhibition of lactate dehydrogenase A (LDHA) induces oxidative stress and inhibits tumor progression. LDHA is a key enzyme in glycolysis, converting pyruvate to lactate and recycling NAD+. It is a target of c-Myc and hypoxia-inducible factor (HIF-1), which are involved in tumor development. Previous studies showed that reducing LDHA expression inhibits tumor initiation, but its role in tumor maintenance and progression was unclear. This study demonstrates that reducing LDHA using siRNA or the small-molecule inhibitor FX11 leads to decreased ATP levels, increased oxidative stress, and cell death. These effects can be partially reversed by the antioxidant N-acetylcysteine (NAC). FX11 also inhibits the progression of human lymphoma and pancreatic cancer xenografts, and when combined with the NAD+ synthesis inhibitor FK866, it induces lymphoma regression. These findings suggest that targeting LDHA with small-molecule inhibitors is a feasible and tolerable treatment for LDHA-dependent tumors. The study highlights the importance of oxidative stress and metabolic phenotyping in cancer biology for therapeutic targeting of cancer energy metabolism. The results indicate that LDHA is essential for tumor progression and that targeting cancer metabolism through small drug-like molecules is achievable. The study also shows that FX11 selectively inhibits LDHA, leading to reduced glycolysis and increased mitochondrial respiration, which contributes to tumor cell death. The findings support the idea that targeting LDHA could be a promising strategy for cancer therapy.Inhibition of lactate dehydrogenase A (LDHA) induces oxidative stress and inhibits tumor progression. LDHA is a key enzyme in glycolysis, converting pyruvate to lactate and recycling NAD+. It is a target of c-Myc and hypoxia-inducible factor (HIF-1), which are involved in tumor development. Previous studies showed that reducing LDHA expression inhibits tumor initiation, but its role in tumor maintenance and progression was unclear. This study demonstrates that reducing LDHA using siRNA or the small-molecule inhibitor FX11 leads to decreased ATP levels, increased oxidative stress, and cell death. These effects can be partially reversed by the antioxidant N-acetylcysteine (NAC). FX11 also inhibits the progression of human lymphoma and pancreatic cancer xenografts, and when combined with the NAD+ synthesis inhibitor FK866, it induces lymphoma regression. These findings suggest that targeting LDHA with small-molecule inhibitors is a feasible and tolerable treatment for LDHA-dependent tumors. The study highlights the importance of oxidative stress and metabolic phenotyping in cancer biology for therapeutic targeting of cancer energy metabolism. The results indicate that LDHA is essential for tumor progression and that targeting cancer metabolism through small drug-like molecules is achievable. The study also shows that FX11 selectively inhibits LDHA, leading to reduced glycolysis and increased mitochondrial respiration, which contributes to tumor cell death. The findings support the idea that targeting LDHA could be a promising strategy for cancer therapy.