Beyond the Warburg Effect: KRAS/MAPK-Driven Uridine Utilization in Glucose-Deprived Pancreatic Ductal Adenocarcinoma

Cancer cells exhibit a significantly altered metabolic phenotype, characterized by a distinctive reliance on glucose to support their growth, survival, and proliferation through a unique energy extraction mechanism. This metabolic reprogramming is epitomized by an increased glucose demand and a preference for lactic fermentation, even in the presence of oxygen, rather than the conventional citric acid cycle utilized by non-cancerous cells. This phenomenon, known as the Warburg Effect, serves as a hallmark of cancer metabolism. The implications of this metabolic shift extend beyond cellular energy dynamics, as it initiates the development of a novel tumor microenvironment characterized by adverse conditions such as hypoxia and glucose scarcity, particularly pronounced in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDA), a notably therapy-resistant malignancy, exemplifies this metabolic adaptation. Under conditions of glucose limitation, PDA cells demonstrate a remarkable ability to utilize uridine as a primary energy substrate, a process regulated by uridine phosphorylase 1 (UPP1). UPP1 plays a central role in metabolizing uridine-derived ribose, thereby supporting central carbon metabolism, maintaining redox homeostasis, and promoting cell survival and proliferation under nutrient-restricted conditions. This metabolic pathway is under the regulatory control of KRAS–MAPK signaling, which is further amplified in response to nutrient deprivation. Consistent with these observations, tumor specimens show elevated UPP1 expression compared to normal tissues, correlating with poor clinical outcomes. The availability of uridine in the tumor microenvironment and its active catabolism within tumor cells underscore the clinical importance of these metabolic processes. Notably, genetic ablation of UPP1 disrupts uridine utilization and significantly suppresses PDA growth in murine models. In summary, this review highlights uridine metabolism as a pivotal compensatory mechanism enabling PDA cells to adapt to nutrient-deprived environments. By influencing the Warburg Effect, uridine utilization integrates nucleotide metabolism with energy production, revealing critical molecular pathways that regulate glucose metabolism in tumor cells. These findings provide novel insights into the metabolic flexibility of PDA and identify potential therapeutic targets for its treatment.