HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma

By virtue of its function as a key metabolic regulator, malignant transformation in the pancreas not only confers high aggressiveness but also disrupts systemic metabolism. However, the causal relationship between metabolic reprogramming and the progression of pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. This study identifies aberrant protein kinase A (PKA) activation in PDAC, correlating with poor prognosis. Mechanistically, downregulation of the transcription factor hematopoietically expressed homeobox (HHEX) represses protein kinase cAMP-dependent type II regulatory subunit beta (PRKAR2B), relieving inhibition on PKA catalytic activity. A high-glucose microenvironment promotes cAMP production, further activating PKA, which then enhances glycolysis via specific upregulation of hexokinase 2 (HK2). <i>In vivo</i>, high glucose synergized with PKA activation to promote metastasis, whereas glycolysis inhibition blocked new metastases. Thus, HHEX-PRKAR2B-mediated PKA activation is a critical hub for PDAC progression, modulated by glucose and reinforcing glycolysis via HK2, revealing novel therapeutic targets for metabolic intervention.