CircRNA circuits orchestrate lactate metabolism in gastrointestinal cancer progression

Circular RNAs (circRNAs) have emerged as pivotal modulators of cancer metabolic reprogramming, orchestrating glycolysis and lactate metabolism to fuel malignant progression. Acting predominantly as competing endogenous RNAs (ceRNAs), circRNAs sequester tumor-suppressor microRNAs, thereby upregulating glycolytic enzymes, transporters, and key metabolic regulators. Across gastric, colorectal, esophageal, pancreatic, and hepatocellular carcinomas, oncogenic circRNAs converge to enhance glucose uptake, lactate production, and ATP generation, sustaining proliferation, metastasis, stemness, and therapy resistance. In contrast, tumor-suppressive circRNAs attenuate glycolytic flux, depriving cancer cells of energy and biosynthetic precursors. Mechanistic diversity-spanning circRNA-microRNA-hexokinase 2 and circRNA-microRNA-lactate dehydrogenase A axes, as well as hypoxia-induced circRNA signaling networks-underscores their cancer-type specificity and potential as precision oncology targets. Despite promising diagnostic and therapeutic implications, challenges remain in delivery, specificity, and functional annotation. Future advances will rely on multi-omics integration, high-throughput functional screening, and validation in patient-derived models to identify clinically actionable circRNA-metabolism regulatory circuits. Mapping these interactions offers not only biomarkers for prognosis and therapy response but also potential intervention points to rewire tumor metabolism.