ArticleCancer communications (London, England)2025
Simvastatin overcomes the pPCK1-pLDHA-SPRINGlac axis-mediated ferroptosis and chemo-immunotherapy resistance in AKT-hyperactivated intrahepatic cholangiocarcinoma.
Article in Cancer communications (London, England), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Advances and challenges in immunotherapy for intrahepatic cholangiocarcinoma based on the tumour immune microenvironment.Clinical and translational medicine · 2026Review
- The circadian architecture of tumor immunity: mechanistic insights and treatment strategies.Biomarker research · 2026Review
- Metabolic reprogramming of myeloid cells in cancer: from lactate-NAMPT axis to AI-guided therapeutics.Experimental & molecular medicine · 2026Review
- Emerging roles of the metabolic regulator 3-hydroxy-3-methylglutaryl coenzyme-CoA reductase in human cancers: From biology to therapeutics.Genes & diseases · 2026Review
- Simvastatin Restores Cisplatin Sensitivity by Suppressing the Caveolin-1-Mediated PI3K/AKT Signaling Pathway in Cisplatin-Resistant Cervical Cancer Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Ferroptosis-autophagy crosstalk in bladder cancer: mechanisms and therapeutic implications.Molecular cancer · 2026Review
- Lactate metabolism-driven tumor heterogeneity and molecular signatures in intrahepatic cholangiocarcinoma.World journal of gastroenterology · 2026Article
- Prognostic Value of Baseline Systemic Immune-Inflammation Index in Advanced Intrahepatic Cholangiocarcinoma Treated with First-Line Gemcitabine-Cisplatin Plus PD-L1 Inhibitor: A Single-Center Retrospective Study.Current oncology (Toronto, Ont.) · 2026Article
- Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review).International journal of molecular medicine · 2026Review
- Low-dose Simvastatin protects pancreatic cancer cells by promoting mitochondrial autophagy through TFEB.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- GLUT3 drives paclitaxel resistance in peritoneal metastatic gastric cancer by promoting H3K18 lactylation-mediated MAPKAP1 transcription to suppress ferroptosis.International journal of biological sciences · 2026Article
- Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review).International journal of oncology · 2026Review
- When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease.Frontiers in cell and developmental biology · 2026Review
- Lactylation in urological malignancies: emerging mechanisms and therapeutic direction.Frontiers in cell and developmental biology · 2026Review
- Roles of lactylation in lipid metabolism and related diseases.Cell death discovery · 2025Review
- Simvastatin overcomes the pPCK1-pLDHA-SPRINGlac axis-mediated ferroptosis and chemo-immunotherapy resistance in AKT-hyperactivated intrahepatic cholangiocarcinoma.Cancer communications (London, England) · 2025Article
- Six-methoxyflavone suppresses CircPIAS1 biogenesis via targeting PTBP1 and, in combination with IFN-γ, promotes ferroptosis in melanoma.Frontiers in pharmacology · 2025Article
- Targeting Lactylation Offers Therapy to Reverse Cell Death Resistance.Drug design, development and therapy · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
backgroundIntrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ-1/KEYNOTE-966 study demonstrated chemo-immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation.
methodsIn vivo metabolic CRISPR screening in a Kras
resultsUnder AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone-4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1-pLDHA-SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)-pPCK1 levels might serve as a biomarker to predict CIT response in ICC.
conclusionThis study identified the pAKT-pPCK1-pLDHA-SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin-based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.
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