LncRNA YIYA drives pancreatic cancer proliferation under high-glucose conditions by reinforcing a RAS-PKM2-dependent Warburg phenotype.

Hyperglycaemia is an independent risk factor for pancreatic cancer (PC). Here, we show that both chronic and intermittent high glucose cause a robust upregulation of the novel lncRNA LINC00538 (YIYA) in pancreatic ductal adenocarcinoma (PDAC) cells. YIYA enhances PDAC cell proliferation in both 2D and 3D culture systems, and its expression shows a positive correlation with poor patient survival. Importantly, knockdown of YIYA attenuates the proliferative effect. Mechanistically, YIYA drives the Warburg phenotype in a KRAS-dependent manner. YIYA physically interacts with KRAS and the glycolytic enzyme pyruvate kinase 2 (PKM2). Notably, YIYA stabilises KRAS by preventing its autophagy-mediated degradation, thereby sustaining a proliferative state. This study identifies YIYA as a glucose-responsive lncRNA that links KRAS signalling to metabolic reprogramming in PDAC.