Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
The KRAS inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS 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. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRAS-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRAS-mutated PDAC.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866490 | PMC |
| http://dx.doi.org/10.1016/j.xcrm.2025.101966 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Multi-omics analyses reveal the regulation mechanisms of organic acid biosynthesis in newly isolated lactic acid bacteria with application in corn biomass fermentation.
Prep Biochem Biotechnol
September 2025
Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China.
Lactic acid bacteria (LAB) are widely used in industrial fermentation due to their versatile metabolic capabilities. This study investigated the molecular mechanisms underlying organic acid biosynthesis in newly isolated YC1-1-4B and PC-C1 strains at two culture intervals and their applications in corn biomass fermentation. YC1-1-4B exhibited faster growth and higher organic acid production (29.
View Article and Find Full Text PDFEnhancing functional properties and analysis of sugar and metabolite composition of juice through fermentation.
Food Chem X
August 2025
School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, China.
fermentation has been shown to provide significant health benefits and safety advantages. This study investigated the impact of fermentation on the physicochemical characteristics, metabolic profiles, and sensory properties of juice (HMJ). fermentation enhanced the physicochemical profile of HMJ by improving bioactive components and increasing the antioxidant activity.
View Article and Find Full Text PDFRestoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
Proc Natl Acad Sci U S A
September 2025
Department of Radiation Oncology, Stanford University, Stanford, CA 94305.
Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation.
View Article and Find Full Text PDFEffects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP] in different neural cell types and brain regions.
Free Radic Biol Med
September 2025
Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614. Electronic address:
Dietary restriction (DR), which slows aging, increases the ratio of reduced glutathione (GSH) to oxidized glutathione disulfide (GSSG) in the brain. DR increases liver cytoplasmic [NADPH]/[NADP] where much of the NADPH is generated by the folate cycle. This could also occur in astrocytes, the neural cell type with the highest folate cycle flux.
View Article and Find Full Text PDFFrom gut to proteomics: the impact of on post-translational modifications in colorectal cancer.
Front Oncol
August 2025
Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
Background: Colorectal cancer (CRC) represents a significant global health challenge. Gut microbiota imbalance and abnormal chromatin modifications play critical roles in the progression of CRC. However, the mechanisms by which they exert their influences, particularly the involvement of ()-mediated post-translational modifications (PTMs), remain inadequately understood.
View Article and Find Full Text PDF