{"id":"doi:10.1002/ctm2.70749","kind":"article","title":"Targeting the CTBP1-CETP axis overcomes ferroptosis resistance in non-small cell lung cancer by altering lipid accumulation","authors":["Chen Y","Wang H","Tan X","Yan C","Liu F","Deng S","Wang C","Xia Y","Xu Z","Wu K","Huang S","Chu Q"],"author_count":12,"year":2026,"published":"2026-08-01","venue":"Clinical and translational medicine","cited_by":0,"doi":"10.1002/ctm2.70749","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1002/ctm2.70749","archive_url":"https://space-kitty.com/papers/doi:10.1002/ctm2.70749","updated":null,"pmid":"42515937","pmcid":"PMC13408231","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13408231/pdf","abstract":"Background Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer mortality. Increasing evidence implicates aberrant cholesterol metabolic reprogramming as a key facilitator of tumour malignancy; however, the mechanistic connections between lipoprotein metabolism and NSCLC pathogenesis remain elusive. Here, we investigate the unrecognised oncogenic role of cholesteryl ester transfer protein (CETP), a central lipid exchange mediator. Methods Serum lipid profiles from 151 NSCLC patients were analysed, and CETP mRNA expression level was evaluated in normal lung (n = 47) and NSCLC tissue (n = 54) and paired NSCLC tissue microarrays (n = 113). Integrated ChIP-seq/RNA-seq analyses, ChIP-qPCR, dual-luciferase reporter and ubiquitination assays were performed to investigate CTBP1-mediated CETP transcription. Functional studies in NSCLC cells, xenograft models and eight patient-derived organoids evaluated the role of the CTBP1-CETP axis in lipid remodelling, ferroptosis and the therapeutic efficacy of obicetrapib alone or combined with RSL3. Results CETP was significantly up-regulated in NSCLC tissues and predicted poor overall survival in both LUAD (HR = 1.46, 95% CI 1.13-1.87, p = .0033) and LUSC (HR = 1.51, 95% CI 1.12-2.01, p = .0067). CTBP1 activated CETP transcription, and CTBP1 ubiquitination further enhanced its transcriptional activity. The CTBP1-CETP axis promoted ferroptosis resistance by lipid accumulation. Obicetrapib phenocopied CETP depletion and synergised with RSL3 to inhibit tumour growth in NSCLC cells, xenografts and patient-derived organoids. Conclusions Our study delineates a novel CTBP1-CETP-lipid droplet-MAPK signalling cascade that couples metabolic rewiring with ferroptosis evasion. These insights establish the CTBP1-CETP axis as a critical cell fate determinant, positioning pharmacological CETP inhibition (e.g., obicetrapib) as a translatable therapeutic vulnerability in lipid-dependent, ferroptosis-resistant NSCLC.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Targeting the CTBP1-CETP axis overcomes ferroptosis resistance in non-small cell lung cancer by altering lipid accumulation\" by Chen Y, Wang H, Tan X et al., https://doi.org/10.1002/ctm2.70749, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"cardiovascular-innovation","name":"Cardiovascular Therapeutics","domain_slug":"medicine"}],"cited_in_dossiers":[]}