biostudies-literatureUnknown6(2)Jiang XLanzhou City Science and Technology BureauFundamental Research Funds for the Central UniversitiesGansu Provincial Science and Technology DepartmentNational Natural Science Foundation of ChinaGansu Provincial Natural Science FoundationThe KRAS^G12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS^G12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS^G12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. LeveragiCell reports. Medicine101966https://www.ebi.ac.uk/biostudies/studies/S-EPMC11866490biostudies-literatureKRAS<sup>G12D</sup>-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.PMC11866490Shi LYang JGuan JDong YQin LZhao BMa YShi WHe QWang KLi MLiu WLi ZXiao LGuan XZhou CJiang XWang TSun HYu ZJiao ZZhou HWu YLong BfalseKRAS<sup>G12D</sup>-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.The KRAS^G12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS^G12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS^G12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveragi2025-01-01T00:00:00Z2025 Feb2026-04-08T19:47:15.878Z2025-04-04T01:11:53.587ZS-EPMC118664903997087310.1016/j.xcrm.2025.101966