Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with mortality projected to rank second in cancer-related deaths by 2030. Gemcitabine is a first-line chemotherapy, but resistance frequently develops, leading to poor prognosis. Metabolic reprogramming, particularly enhanced glycolysis driven by hypoxia and HIF-1α activation, is a key mechanism of gemcitabine resistance. Statins, commonly used cholesterol-lowering drugs that inhibit HMG-CoA reductase, have demonstrated potential metabolic and anti-cancer effects with an established safety profile. This study investigated whether statins could overcome gemcitabine resistance in PDAC by targeting glycolytic adaptation. Methods: Gemcitabine-resistant PDAC cell lines (MIA PaCa-2 and BxPC-3) and patient-derived 3D organoids were treated with simvastatin alone or combined with gemcitabine. Outcomes included cell viability, apoptosis, migration, invasion, and glycolytic activity (measured by extracellular acidification rate ECAR and lactate production). Expression of glycolysis-related genes HIF-1α, HK2, and LDHA was measured by RT-qPCR and Western blotting. Pharmacological modulation of HIF-1α was used to validate the mechanism. Clinical significance was assessed via EUS-FNA samples from 50 patients with PDAC treated with Gemcitabine and transcriptomic data from The Cancer Genome Atlas (TCGA). Results: Simvastatin reduced the viability of Gemcitabine-resistant PDAC cells compared with parental cell lines (IC50: 20-21 μM vs. 37-39 μM in parental cells; p0.01) and showed synergy with Gemcitabine (Bliss scores: 5.5 and 4.29) and markedly enhanced anti-tumor activity, reducing viability by 41.7% and 44.4%, respectively. The combination significantly suppressed migration and invasion and increased apoptosis (p0.001), accompanied by increased cleaved PARP and caspase-3. Resistant cells exhibited elevated glycolysis, and simvastatin, especially in combination with Gemcitabine, reduced lactate, ECAR, and expression of HIF-1α, HK2, and LDHA at both mRNA and protein levels (p0.01), mimicking HIF-1α inhibition. In two PDAC organoids, combination therapy disrupted structure and reduced viability while downregulating glycolytic genes. Clinically, high HIF-1α/HK2/LDHA expression correlated with Gemcitabine nonresponse and worse PFS/OS in both our gemcitabine-treated cohort and TCGA dataset. Conclusion: Statins restore gemcitabine sensitivity in PDAC by suppressing HIF-1α-driven glycolytic reprogramming, reversing the metabolic adaptations responsible for chemoresistance. With their proven safety, affordability, and wide availability, statins offer a promising, immediately translatable approach to improve outcomes in gemcitabine-resistant PDAC. Citation Format: Takayuki Noma, Mitsuo Shimada, Ajay Goel. Metabolic reprogramming via statin repurposing: A strategy to reverse the Warburg effect and overcome gemcitabine resistance in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3123.
Noma et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: