The study investigates the role of lactate dehydrogenase A (LDHA) in tumor progression and its therapeutic potential. LDHA, encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1), is upregulated in many cancer cells due to genetic alterations and tumor hypoxia. Previous studies have shown that reducing LDHA expression can inhibit tumor initiation, but its role in tumor maintenance and progression was not well understood. The authors used siRNA and a small-molecule inhibitor, FX11, to reduce LDHA levels, which led to increased oxygen consumption, oxidative stress, and cell death. FX11 also inhibited the progression of human lymphoma and pancreatic cancer xenografts, particularly in hypoxic regions. When combined with the NAD+ synthesis inhibitor FK866, FX11 induced significant regression of lymphoma. These findings suggest that targeting LDHA with small molecules is a viable therapeutic approach for LDHA-dependent tumors, providing a new strategy to combat cancer energy metabolism.The study investigates the role of lactate dehydrogenase A (LDHA) in tumor progression and its therapeutic potential. LDHA, encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1), is upregulated in many cancer cells due to genetic alterations and tumor hypoxia. Previous studies have shown that reducing LDHA expression can inhibit tumor initiation, but its role in tumor maintenance and progression was not well understood. The authors used siRNA and a small-molecule inhibitor, FX11, to reduce LDHA levels, which led to increased oxygen consumption, oxidative stress, and cell death. FX11 also inhibited the progression of human lymphoma and pancreatic cancer xenografts, particularly in hypoxic regions. When combined with the NAD+ synthesis inhibitor FK866, FX11 induced significant regression of lymphoma. These findings suggest that targeting LDHA with small molecules is a viable therapeutic approach for LDHA-dependent tumors, providing a new strategy to combat cancer energy metabolism.