Clinical and Translational Medicine · Published 2026-07-27 · DOI 10.1002/ctm2.70749
Yanjie Chen, Heng Wang, Ximin Tan, Chenxi Yan, Fangfang Liu, Shuxuan Deng, Chengyan Wang, Yangchen Xia, Zhaolin Xu, Kongming Wu, Shanshan Huang, Qian Chu
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 from DOAJ. Public domain (CC0 1.0).
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Chen, Y., Wang, H., Tan, X., et al. (2026). Targeting the CTBP1–CETP axis overcomes ferroptosis resistance in non‐small cell lung cancer by altering lipid accumulation. Clinical and Translational Medicine. https://doi.org/10.1002/ctm2.70749