Revisiting the Warburg Effect: Modern Understanding, Existing Misconceptions and Evolving Concepts in Cancer Metabolism

The Warburg effect, classically defined as the preferential use of glycolysis by cancer cells in the presence of oxygen, has been a central concept in cancer biology since a long time. Otto Warburg had originally proposed that defective mitochondrial respiration was the primary cause of aerobic glycolysis in cancer cells. While this hypothesis profoundly influenced early cancer metabolism research, it has now become increasingly clear that this interpretation has gaping. Advances in biochemistry, molecular biology and metabolomics demonstrate that mitochondria in many cancers are functional and play essential roles in biosynthesis, signaling and energy production. Aerobic glycolysis in cancer cells is now recognized as an adaptive metabolic strategy that supports rapid proliferation by providing metabolic intermediates, maintaining redox balance, and enabling cellular signaling rather than maximizing ATP yield. This review discusses the Warburg effect through the lens of modern cancer metabolism. It contrasts classical misconceptions with current evidences, discusses key regulatory pathways like HIF-1α, PI3K/Akt/mTOR, c-Myc and PKM2, and examine the central role of lactate as both a metabolic fuel and a signaling molecule. It further explores metabolic heterogeneity, the reverse Warburg effect, immune–metabolic interactions, and the relevance of oxidative phosphorylation in cancer. Finally, some unresolved questions are highlighted that is critical for future understanding of cancer metabolism.