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

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.

Keywords

CETP / CTBP1 / ferroptosis / lipid accumulation / non-small cell lung cancer / obicetrapib

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: gLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.

[2] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2): 115-132.

[3] Chen Z, Fillmore CM, Hammerman PS, et al. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014; 14(8): 535-546.

[4] Patz EF Jr, Swensen SJ, Herndon JE 2nd. Estimate of lung cancer mortality from low-dose spiral computed tomography screening trials: implications for current mass screening recommendations. J Clin Oncol. 2004; 22(11): 2202-2206.

[5] Herbst RSHJ, Lippman SM, Lung cancer. N Engl J Med. 2008; 359: 1367-1380

[6] Rami-Porta RNK, Giroux DJ, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2024; 19(7): 1007-1027.

[7] Broadfield LA, Pane AA, Talebi A, et al. Lipid metabolism in cancer: new perspectives and emerging mechanisms. Dev Cell. 2021; 56(10): 1363-1393.

[8] Guilbaud E, Barouillet T, Ilie M, et al. Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion. Cell Stem Cell. 2023; 30(6): 800-817.

[9] Liu X, Lv M, Zhang W, et al. Dysregulation of cholesterol metabolism in cancer progression. Oncogene. 2023; 42(45): 3289-3302.

[10] Jin HR, Wang J, Wang ZJ, et al. Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics. J Hematol Oncol. 2023; 16(1): 103.

[11] Kuzu OF, Noory MA, Robertson GP, The role of cholesterol in cancer. Cancer Res. 2016; 76(8): 2063-2070.

[12] Schmidt HM, Jarrett KE, de Aguiar , Vallim TQ, et al. Pathways and molecular mechanisms governing LDL receptor regulation. Circ Res. 2025; 136(8): 902-919.

[13] Dai CL, Qiu ZY, Wang AQ, et al. Targeting cholesterol metabolism: a promising therapy strategy for cancer. Acta Pharmacol Sin. 2025; 46(8): 2093-2104.

[14] Jiang S, Wang X, Song D, et al. Cholesterol induces epithelial-to-mesenchymal transition of prostate cancer cells by suppressing degradation of EGFR through APMAP. Cancer Res. 2019; 79(12): 3063-3075.

[15] Hu Z, Zheng Y, Zheng J, et al. Effect of body mass index and cholesterol-rich apolipoprotein-B-containing lipoproteins on clinical outcome in NSCLC patients treated with immune checkpoint inhibitors-based therapy: a retrospective analysis. Cancer Med. 2024; 13(11):e7241.

[16] Tang M, Song C, Zhang Y, et al. Levels of pretreatment blood lipids are prognostic factors in advanced NSCLC patients treated with anlotinib. Lipids Health Dis. 2021; 20(1): 165.

[17] Rader DJ, deGoma EM, Future of cholesteryl ester transfer protein inhibitors. Annu Rev Med. 2014; 65: 385-403.

[18] Schmidt AF, Hunt NB, Gordillo-Maranon M, et al. Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease. Nat Commun. 2021; 12(1): 5640.

[19] Laufs U, Speer T, CETP inhibitors revisited. Eur Heart J. 2022; 43(14): 1425-1427.

[20] Nicholls SJ, Ditmarsch M, Kastelein JJ, et al. Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nat Med. 2022; 28(8): 1672-1678.

[21] Sarraju A, Brennan D, Hayden K, et al. Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2025; 405(10491): 1757-1768.

[22] Nicholls SJ, Nelson AJ, Ditmarsch M, et al. Safety and efficacy of obicetrapib in patients at high cardiovascular risk. N Engl J Med. 2025; 393(1): 51-61.

[23] Stankiewicz TR, Gray JJ, Winter AN, et al. C-terminal binding proteins: central players in development and disease. Biomol Concepts. 2014; 5(6): 489-511.

[24] Chen Z. The transrepression and transactivation roles of CtBPs in the pathogenesis of different diseases. J Mol Med (Berl). 2021; 99(10): 1335-1347.

[25] Filograna A, De Tito S, Monte ML, et al. Identification and characterization of a new potent inhibitor targeting CtBP1/BARS in melanoma cells. J Exp Clin Cancer Res. 2024; 43(1): 137.

[26] Ding B, Yuan F, Damle PK, et al. CtBP determines ovarian cancer cell fate through repression of death receptors. Cell Death Dis. 2020; 11(4): 286.

[27] Deng Y, Liu J, Han G, et al. Redox-dependent Brca1 transcriptional regulation by an NADH-sensor CtBP1. Oncogene. 2010; 29(50): 6603-6608.

[28] Chinnadurai G, The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res. 2009; 69(3): 731-734.

[29] Tai L, Zhu D, Tang P, et al. Reciprocal stabilization of CtBP and TRIM28 represses autophagy to promote metastasis. Nat Struct Mol Biol. 2025; 32(8): 1408-1423.

[30] Charles N, Birts AB, Matthew Darley, et al. p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators. Science Signaling. 2020; 13(630): eaau9529.

[31] Sahu SK, Tiwari N, Pataskar A, et al. FBXO32 promotes microenvironment underlying epithelial-mesenchymal transition via CtBP1 during tumour metastasis and brain development. Nat Commun. 2017; 8(1): 1523.

[32] Deng Y, Guo W, Xu N, et al. CtBP1 transactivates RAD51 and confers cisplatin resistance to breast cancer cells. Mol Carcinog. 2020; 59(5): 512-519.

[33] Paliwal S, Ho N, Parker D, et al. CtBP2 promotes human cancer cell migration by transcriptional activation of Tiam1. Genes Cancer. 2012; 3(7-8): 481-490.

[34] Jin W, Scotto KW, Hait WN, et al. Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells. Biochem Pharmacol. 2007; 74(6): 851-859.

[35] Zhang Z, Zhou H, Gu W, et al. CGI1746 targets sigma(1)R to modulate ferroptosis through mitochondria-associated membranes. Nat Chem Biol. 2024; 20(6): 699-709.

[36] Cheff DM, Huang C, Scholzen KC, et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 2023; 62:102703.

[37] Huber J, Boechzelt H, Karten B, et al. Oxidized cholesteryl linoleates stimulate endothelial cells to bind monocytes via the extracellular signal-regulated kinase 1/2 pathway. Arterioscler Thromb Vasc Biol. 2002; 22(4): 581-586.

[38] Chen X, Liu C, Zhao R, et al. Synergetic and antagonistic molecular effects mediated by the feedback loop of p53 and JNK between saikosaponin D and SP600125 on lung cancer A549 cells. Mol Pharm. 2018; 15(11): 4974-4984.

[39] Wu J, Zhao S, Tang Q, et al. Activation of SAPK/JNK mediated the inhibition and reciprocal interaction of DNA methyltransferase 1 and EZH2 by ursolic acid in human lung cancer cells. J Exp Clin Cancer Res. 2015; 34(1): 99:

[40] Fang YWJ, Wang G, Zhou C, et al. Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer. Oncotarget. 20178(16): 26702-26717.

[41] Huang H, Li X, Luo J, et al. FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia. Science Advances. 2025; 11(22):eadq3052.

[42] Liu Q, Yang Y, Wu M, et al. Hub gene ELK3-mediated reprogramming lipid metabolism regulates phenotypic switching of pulmonary artery smooth muscle cells to develop pulmonary arterial hypertension induced by PM(2.5). J Hazard Mater. 2024; 465:133190.

[43] Zhuang T, Liu J, Chen X, et al. Endothelial Foxp1 suppresses atherosclerosis via modulation of Nlrp3 inflammasome activation. Circ Res. 2019; 125(6): 590-605.

[44] Ling J, Brey C, Schilling M, et al. Defective lipid metabolism associated with mutation in klf-2 and klf-3: important roles of essential dietary salts in fat storage. Nutr Metab (Lond). 2017; 14: 22.

[45] Cao L, Sun W, Chen X, et al. Adipocyte-specific Zeb1 downregulation remodels the tumor-associated adipose microenvironment to facilitate female breast cancer progression. Nat Commun. 2025; 16(1): 6011.

[46] Schwab A, Rao Z, Zhang J, et al. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat Cell Biol. 2024; 26(9): 1470-1481.

[47] Li F, Yu H, Zhang Y, et al. F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression. Nat Commun. 2025; 16(1): 4060.

[48] Wu J, Wen T, Marzio A, et al. FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression. Cell Death Dis. 2024; 15(4): 282.

[49] Stockwell BR, Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022; 185(14): 2401-2421.

[50] Qiu B, Zandkarimi F, Bezjian CT, et al. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis. Cell. 2024; 187(5): 1177-1190.

[51] Calhoon D, Sang L, Ji F, et al. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis. Nature. 2025; 644(8077): 799-808.

[52] Chen Y, Fang ZM, Yi X, et al. The interaction between ferroptosis and inflammatory signaling pathways. Cell Death Dis. 2023; 14(3): 205.

[53] Zhao P, Yin S, Qiu Y, et al. Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance. Molecular Cancer. 2025; 24(1): 23.

[54] Zheng Y, Liu F, Huang Y, et al. SNORA58 facilitates radioresistance via suppressing JNK1-mediated ferroptosis in esophageal squamous cell carcinoma. Adv Sci (Weinh). 2025; 12(40):e08515.

[55] Xue X, Ma L, Zhang X, et al. Tumour cells are sensitised to ferroptosis via RB1CC1-mediated transcriptional reprogramming. Clin Transl Med. 2022; 12(2):e747.

[56] Wang Y, Hu J, Wu S, et al. Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases. Signal Transduction and Targeted Therapy. 2023; 8(1): 449.

[57] Tsai T, Wu S, Lai Y, et al. CD44-hyaluronan mediating endocytosis of iron-platinum alloy nanoparticles induces ferroptotic cell death in mesenchymal-state lung cancer cells with tyrosine kinase inhibitor resistance. Acta Biomater. 2024; 186: 396-410.

[58] Deng H, Liang WY, Chen LQ, et al. CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice. JCI Insight. 2024; 9(8):e173205.

[59] Raposo HF, Forsythe P, Chausse B, et al. Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity. Metabolism. 2021; 114:154429.

[60] Felix CE, Vogel ABC-F, Schulze Almut, Lipids as mediators of cancer progression and metastasis. Nat Cancer. 2024; 5(1): 16-29.

[61] Gu Q, Wang Y, Yi P, et al. Theoretical framework and emerging challenges of lipid metabolism in cancer. Semin Cancer Biol. 2025; 108: 48-70.

[62] Bleve A, Incerti M, Consonni FM, et al. RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression. Cancer Discov. 2025; 5: 1505-1525.

[63] Sun L, Ma Z, Zhao X, et al. LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy. J Immunother Cancer. 2024; 12(1):e008367.

[64] Wu X, Xu M, Geng M, et al. Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies. Signal Transduct Target Ther. 2023; 8(1): 220.

[65] Caramel J, Ligier M, Puisieux A, Pleiotropic roles for ZEB1 in cancer. Cancer Res. 2018; 78(1): 30-35.

[66] Jin H, Park SY, Lee JE, et al. GTSE1-driven ZEB1 stabilization promotes pulmonary fibrosis through the epithelial-to-mesenchymal transition. Mol Ther. 2024; 32(11): 4138-4157.

[67] Dong D, Zhou Z, Zhu M, et al. STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer. Nat Commun. 2025; 16(1): 7815.

[68] Zhou B, Fang F, Zhang Y, et al. Core transcriptional regulatory circuitry molecule ZNF217 promotes AML cell proliferation by up-regulating MYB. Int J Biol Sci. 2025; 21(5): 1966-1983.

Rights & permissions

2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.