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INTERNATIONAL CONGRESS OF

CancerGenetics

• Revisiting the Warburg Effect: Metabolic Plasticity, Lactate Signaling, and Therapeutic Opportunities in Cancer

• Yalda Mozaffari ,^1,* Mahsa Shahrashoob,²
  1. Department of Microbiology, TeMS.C., Islamic Azad University, Tehran, Iran
  2. Department of Biochemistry and Biophysics, TeMS.C., Islamic Azad University, Tehran, Iran
  
  
  
• Introduction: The Warburg effect is a hallmark of cancer matabolism characterized by increased glycolysis and lactate production despite sufficient oxygen. Although originally attributed to mitochondrial dysfunction, current evidence indicates that mitochondria remain functional in most cancers, suggesting that the Warburg effect represents a regulated metabolic adaptation driven by oncogenic signaling and the tumor microenvironment rather than a metabolic defect. Warburg-like metabolic reprogramming has also been observed in several rapidly proliferating normal cell types. This review summarizes current evidence on the molecular mechanisms of the Wraburg effect, its role in tumor progression and chemoresistance, and its therapeutic implications.
• Methods: This review is based on recent peer-reviewed English-language articles focusing on cancer metabolism, the Warburg effect, mitochondrial function, glycolytic regulation, metabolic plasticity, lactate-mediated protein lactylation, and the therapeutic targeting of glycolisis. Key sources include Zhang et al. (2025) on lactylation and chemoresistance, Martins Pinto et al. (2023) on oxidative phosphorylation, and Papaneophytou (2024) on reinterpretation of the Warburg effect, along with additional studies on glycolysis inhibition and drug resistance.
• Results: Current evidence indicates that cancer metabolism is highly dynamic rather than a permanent shift from oxidative phosphorylation (OXPHOS) to glycolysis. In most tumors, these metabolic pathways coexist, with their relative contributions varying according to tumor type and microenvironmental conditions. This metabolic flexibility enables cancer cells to adapt to metabolic stress and sustain proliferation. Lactate is no longer considered a metabolic waste product but an active signaling molecule that mediates histone and non-histone protein lactylation, thereby regulating gene expression. Evidence suggest that lactylation contributes to tumor progression, immune modulation, and chemoresistance, although its precise role across different cancer types remains under investigation. Targeting glycolysis has emerged as a promising therapeutic strategy. However, clinical efficacy remains limited because cencer cells compensate through metabolic plasticity and alternative pathways, indicataing that combination therapies may be more effective than glycolysis inhibition alone. Warburg-like metabolic reprogramming has also been observed in several normal proliferative cell types, suggesting that the Warburg effect is not exclusive to cancer. Furthermore, wether the Warburg effect is a driver of tumor progression or primarily an adaptive response to oncogenic signaling and the tumor microenvironment remains unresolved, highlighting the need for further investigation.
• Conclusion: The Warburg effect should be viewed as a dynamic and adaptive metabolic strategy rather than a metabolic defect or a phenomenon exclusive to cancer. Its significance extends beyond energy production to include biosynthesis, redox balance, and epigenetic regulation via lactate signaling. Although targeting cancer metabolism represents an attractive therapeutic approach, metabolic plasticity and compensatory activation of oxidative phosphorylation substantially limit the efficacy of glycolysis-directed therapies. Furthermore, because similar metabolic processes also occur in several normal physiological settings, future therapeutic strategies must achieve sufficient selectivity to minimize toxicity. Future research should focus on metabolic heterogeneity and combination therapies targeting multiple pathways. A deeper understanding of metabolic plasticity may lead more effective and personalized cancer tratments.
• Keywords: Warburg effect; Cancer metabolism; Glycolysis; Lactate; Metabolic plasticity; Chemoresistance