Revisiting the Warburg Effect: Linking Hydrogen Sulfide to the Central Metabolic Network in Cancer

Abstract The Warburg effect is a metabolic process in which cancer cells prefer glycolysis over aerobic respiration even in the presence of oxygen. This metabolic shift allows cancer cells to use glycolytic intermediates for synthesizing DNA, RNA, and proteins, enabling rapid proliferation. Among other known regulators of cancer metabolism, hydrogen sulfide (H 2 S), a gasotransmitter produced endogenously inside the cell, has emerged as a key player. H 2 S mediates protein sulfhydration, a posttranslational modification resulting in changes of protein dynamics to modulate the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2), lactate dehydrogenase A, and glyceraldehyde-3-phosphate dehydrogenase. Sulfhydration of PKM2 at cysteine 326, in particular, promotes its transition from an active tetrameric state to a less active dimeric state, redirecting glucose metabolism to glycolysis and facilitating tumor growth. This review highlights the importance of H 2 S-mediated sulfhydration in cancer metabolism and advocates for further exploration of this pathway as a target for anticancer drug development. A deeper understanding of the biochemical pathways underlying cancer metabolism will facilitate the design of highly selective and potent inhibitors, ultimately improving therapeutic outcomes for cancer patients.