Metabolic dysfunctions in pancreatic ductal adenocarcinoma: Pathogenic mechanisms and therapeutic implications

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy characterized by a dismal prognosis and profound resistance to conventional therapies. Emerging evidence highlights systemic metabolic dysfunctions including obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty pancreatic disease (NAFPD) as critical drivers of PDAC initiation, progression and chemoresistance. This review integrates current knowledge on the intricate interplay between metabolic alterations and PDAC biology, focusing on the therapeutic and chemopreventive potential of repurposed metabolic modulators (specifically statins and antidiabetic agents) and novel metabolic pathway inhibitors currently under clinical evaluation. Statins exert prominent antitumor effects in preclinical models by disrupting the mevalonate pathway, impairing Ras prenylation, and reprogramming cholesterol metabolism; however, epidemiological data regarding risk reduction remain inconsistent. Parallel to lipid pathways, glucose homeostasis dictates tumor behavior. T2DM acts as both a potent risk factor and an early paraneoplastic indicator through new-onset diabetes. Among antidiabetic drugs, metformin attenuates PDAC progression via insulin-lowering and AMPK-mediated pathways, though its survival benefits are often obscured in clinical trials by methodological challenges. Conversely, hyperinsulinemia driven by exogenous insulin or secretagogues exacerbates PDAC risk, while incretin-based therapies yield conflicting outcomes. Notably, novel strategies targeting metabolic vulnerabilities, such as SGLT2 inhibition combined with metformin, show promise in targeting chemoresistant, nutrient-deprived tumor zones. Ultimately, integrating metabolic profiling, prescription history, and molecular biomarkers into clinical practice is essential to advance risk stratification and precision oncology. Overcoming tumor metabolic plasticity in contemporary clinical trials will require a shift from single-node therapies towards rational, biomarker-guided combination strategies.