Revisiting the biological role of the Warburg effect: Evolving perspectives on cancer metabolism

Abstract

Cancer cells exhibit metabolic reprogramming towards a glycolysis-dominant profile. This shift, known as the Warburg effect, enhances cancer cell survival, growth, and metastasis by increasing glucose uptake and lactate production. It also meets the high anabolic demands of proliferation by providing important biosynthetic precursors. Despite its long-standing discovery, the origins and roles of the Warburg effect in cancer remain unclear. Recent research has provided deeper insights into its cellular origins and involvement in cancer progression and metastasis. Therefore, this review aims to provide a comprehensive and updated understanding of the significance of glycolysis in cancer. Initially, a brief overview of the glycolytic pathway will be presented, followed by an in-depth discussion of how this pathway is altered in cancer, its biological significance, and its regulatory mechanisms. We highlight that lactate production in cancer cells may not solely reflect a metabolic inefficiency, but rather a compensatory mechanism to regenerate cytosolic NAD⁺ when mitochondrial NADH shuttles become saturated, thereby sustaining glycolytic flux under rapid proliferative demands. Finally, the review will explore the translational implications of glycolysis research in the clinical context.