Targeting the CTBP1–CETP axis overcomes ferroptosis resistance in non‐small cell lung cancer by altering lipid accumulation

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.