Identification and validation of prognostic genes associated with integrative stress response in lung adenocarcinoma and construction of the risk models

identification-and-validation-of-prognostic-genes-associated-with-integrative-stress-response-in-lung-adenocarcinoma-and-construction-of-the-risk-models
Identification and validation of prognostic genes associated with integrative stress response in lung adenocarcinoma and construction of the risk models

References

  1. Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 74, 229–263 (2024).

    Google Scholar 

  2. Zhang, W. et al. Identification of cuproptosis and immune-related gene prognostic signature in lung adenocarcinoma. Front. Immunol. 14, 1179742 (2023).

    Google Scholar 

  3. Hao, D. et al. The single-cell immunogenomic landscape of B and plasma cells in early-stage lung adenocarcinom. Cancer Discov. 12, 2626–2645 (2022).

    Google Scholar 

  4. Lin, Y. et al. Progress in single-cell RNA sequencing of lung adenocarcinoma. Zhongguo Fei Ai Za Zhi. 24, 434–440 (2021).

    Google Scholar 

  5. Hu, R. et al. ISR Inhibition reverses pancreatic β-cell failure in Wolfram syndrome models. Cell. Death Differ. 31, 322–334 (2024).

    Google Scholar 

  6. Koromilas, A. E. Roles of the translation initiation factor eIF2α serine 51 phosphorylation in cancer formation and treatment. Biochim. Biophys. Acta. 1849, 871–880 (2015).

    Google Scholar 

  7. Ghaddar, N. et al. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Nat. Commun. 12, 4651 (2021).

    Google Scholar 

  8. Albert, A. E. et al. Adaptive protein translation by the integrated stress response maintains the proliferative and migratory capacity of lung adenocarcinoma cells. Mol. Cancer Res. 17, 2343–2355 (2019).

    Google Scholar 

  9. Koromilas, A. E. The integrated stress response in the induction of mutant KRAS lung carcinogenesis: mechanistic insights and therapeutic implications. Bioessays 44, e2200026 (2022).

    Google Scholar 

  10. Rao, W. et al. A three-subtype prognostic classification based on base excision repair and oxidative stress genes in lung adenocarcinoma and its relationship with tumor microenvironment. Sci. Rep. 15, 16647 (2025).

    Google Scholar 

  11. Wan, L. et al. Identification of endoplasmic reticulum stress-related signature characterizes the tumor microenvironment and predicts prognosis in lung adenocarcinoma. Sci. Rep. 13, 19462 (2023).

    Google Scholar 

  12. Lin, L. et al. Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma. Front. Immunol. 13, 906420 (2022).

    Google Scholar 

  13. Lior, C. et al. Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response. Cell. Rep. 43, 114236 (2024).

    Google Scholar 

  14. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Google Scholar 

  15. Wang, J. et al. PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma. Front. Immunol. 13, 1052692 (2022).

    Google Scholar 

  16. Gu, Z. Complex heatmap visualization. Imeta 1, e43 (2022).

    Google Scholar 

  17. Chen, H. & Boutros, P. C. VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinform. 12, 35 (2011).

    Google Scholar 

  18. Wu, T. et al. ClusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov. (Camb). 2, 100141 (2021).

    Google Scholar 

  19. Kanehisa, M., Sato, Y., Kawashima, M., Furumichi, M. & Tanabe, M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 44, D457–462 (2016).

    Google Scholar 

  20. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).

    Google Scholar 

  21. Liu, P., Xu, H., Shi, Y., Deng, L. & Chen, X. Potential molecular mechanisms of plantain in the treatment of gout and hyperuricemia based on network pharmacology. Evid Based Complement Alternat Med. 2020, 3023127 (2020).

  22. Shi, Y. et al. Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy. Apoptosis 28, 1423–1435 (2023).

    Google Scholar 

  23. Li, Y., Lu, F. & Yin, Y. Applying logistic LASSO regression for the diagnosis of atypical Crohn’s disease. Sci. Rep. 12, 11340 (2022).

    Google Scholar 

  24. Li, D. & Lyu, G. Prognostic implications and therapeutic potential of MXD genes in gastric cancer. Curr. Med. Chem. (2025).

  25. Moncrieff, J. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol. Psychiatry. 28, 3243–3256 (2023).

    Google Scholar 

  26. Lin, Z. et al. Comprehensive analysis of copper-metabolism-related genes about prognosis and immune microenvironment in osteosarcoma. Sci. Rep. 13, 15059 (2023).

    Google Scholar 

  27. Mayakonda, A., Lin, D. C., Assenov, Y., Plass, C. & Koeffler, H. P. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 28, 1747–1756 (2018).

    Google Scholar 

  28. Dong, B. et al. Identification of a prognostic signature associated with the homeobox gene family for bladder cancer. Front. Mol. Biosci. 8, 688298 (2021).

    Google Scholar 

  29. Zheng, J. et al. Integrative analysis of multi-omics identified the prognostic biomarkers in acute myelogenous leukemia. Front. Oncol. 10, 591937 (2020).

    Google Scholar 

  30. Maeser, D., Gruener, R. F. & Huang, R. S. OncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform. 22, (2021).

  31. Wang, L. et al. Cuproptosis related genes associated with Jab1 shapes tumor microenvironment and pharmacological profile in nasopharyngeal carcinoma. Front. Immunol. 13, 989286 (2022).

    Google Scholar 

  32. Chen, B., Khodadoust, M. S., Liu, C. L., Newman, A. M. & Alizadeh, A. A. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol. Biol. 1711, 243–259 (2018).

    Google Scholar 

  33. Yang, Y., Yi, X., Cai, Y., Zhang, Y. & Xu, Z. Immune-associated gene signatures and subtypes to predict the progression of atherosclerotic plaques based on machine learning. Front. Pharmacol. 13, 865624 (2022).

    Google Scholar 

  34. Møller, P. L. et al. Predicting the presence of coronary plaques featuring high-risk characteristics using polygenic risk scores and targeted proteomics in patients with suspected coronary artery disease. Genome Med. 16, 40 (2024).

    Google Scholar 

  35. Hu, F. F., Liu, C. J., Liu, L. L., Zhang, Q. & Guo, A. Y. Expression profile of immune checkpoint genes and their roles in predicting immunotherapy response. Brief Bioinform. 22, (2021).

  36. Xue, C. et al. Prediction of hepatocellular carcinoma prognosis and immunotherapeutic effects based on tryptophan metabolism-related genes. Cancer Cell. Int. 22, 308 (2022).

    Google Scholar 

  37. Brinkman, E. K. & van Steensel, B. Rapid quantitative evaluation of CRISPR genome editing by TIDE and TIDER. Methods Mol. Biol.. 1961, 29–44 (2019).

  38. Zhang, H., Meltzer, P. & Davis, S. RCircos: an R package for circos 2D track plots. BMC Bioinform. 14, 244 (2013).

    Google Scholar 

  39. Yu, G. et al. GOSemSim: an R package for measuring semantic similarity among GO terms and gene products. Bioinformatics 26, 976–978 (2010).

    Google Scholar 

  40. He, Q. et al. Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2/System xc-/GPX4 axis. Biomed. Pharmacother. 157, 113915 (2023).

    Google Scholar 

  41. Cheng, F. et al. Shortened relative leukocyte telomere length is associated with prevalent and incident cardiovascular complications in type 2 diabetes: analysis from the Hong Kong diabetes register. Diabetes Care. 43, 2257–2265 (2020).

    Google Scholar 

  42. Chang, J. et al. Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma. J. Transl Med. 21, 191 (2023).

    Google Scholar 

  43. Yuan, S. et al. Smoking, alcohol consumption, and 24 Gastrointestinal diseases: Mendelian randomization analysis. Elife 12, (2023).

  44. Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).

    Google Scholar 

  45. Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).

    Google Scholar 

  46. Serveaux-Dancer, M. et al. Pathological implications of receptor for advanced glycation End-Product (AGER) gene polymorphism. Dis. Markers. 2019, 2067353 (2019).

  47. Awan, U. N. et al. RAGE signalling contributes to oxidative stress and inflammation in knee osteoarthritis patients with metabolic syndrome. Clin. Exp. Rheumatol. 42, 2258–2264 (2024).

    Google Scholar 

  48. Sarang, S. S., Cahill, C. M. & Rogers, J. T. Gene expression analysis and validation of a novel biomarker signature for early-stage lung adenocarcinoma. Biomolecules. 15, (2025).

  49. Yang, J. et al. Advanced glycation end products’ receptor DNA methylation associated with immune infiltration and prognosis of lung adenocarcinoma and lung squamous cell carcinoma. Genet. Res. 2023, 7129325 (2023).

  50. Zhuang, G. D. et al. Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis via suppression of AGEs/RAGE/NF-κB pathways. J. Ethnopharmacol. 337, 118787 (2025).

    Google Scholar 

  51. Chu, X. et al. Fucoidan ameliorates lipid accumulation, oxidative stress, and NF-κB-mediated inflammation by regulating the PI3K/AKT/Nrf2 signaling pathway in a free fatty acid-induced NAFLD spheroid model. Lipids Health Dis. 24, 55 (2025).

    Google Scholar 

  52. Alicea Pauneto, C. D. M. et al. Intra-tumoral hypoxia promotes CD8(+) T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4. Immunity 58, 2489–2504e2488 (2025).

    Google Scholar 

  53. Qiao, Y. et al. High glucose stimulates tumorigenesis in hepatocellular carcinoma cells through AGER-dependent O-GlcNAcylation of c-Jun. Diabetes 65, 619–632 (2016).

    Google Scholar 

  54. Nagarajan, S., Rosenbaum, J. & Joks, R. The relationship between allergic Rhinitis, Asthma, and cardiovascular disease in the National Health Interview Surveys (NHIS), 1999–2018. J. Allergy Clin. Immunol. Pract. 12, 1509–1519e1504 (2024).

    Google Scholar 

  55. Zhang, N., Liao, H., Lin, Z. & Tang, Q. Insights into the role of glutathione peroxidase 3 in non-neoplastic diseases. Biomolecules. 14, (2024).

  56. Zhang, X. et al. An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer. Int. J. Oncol. 36, 405–414 (2010).

    Google Scholar 

  57. Liu, R. et al. Neutrophil infiltration associated genes on the prognosis and tumor immune microenvironment of lung adenocarcinoma. Front. Immunol. 14, 1304529 (2023).

    Google Scholar 

  58. Bramble, M. S. et al. Glutathione peroxidase 3 is a potential biomarker for Konzo. Nat. Commun. 15, 7811 (2024).

    Google Scholar 

  59. Liu, K., Jin, M., Xiao, L., Liu, H. & Wei, S. Distinct prognostic values of mRNA expression of glutathione peroxidases in non-small cell lung cancer. Cancer Manag Res. 10, 2997–3005 (2018).

    Google Scholar 

  60. Sharma, S. S. & Dixit, N. K. Somatotype of athletes and their performance. Int. J. Sports Med. 6, 161–162 (1985).

    Google Scholar 

  61. Zhang, G., Wang, X., Rothermel, B. A., Lavandero, S. & Wang, Z. V. The integrated stress response in ischemic diseases. Cell. Death Differ. 29, 750–757 (2022).

    Google Scholar 

  62. Lu, H. J., Koju, N. & Sheng, R. Mammalian integrated stress responses in stressed organelles and their functions. Acta Pharmacol. Sin. 45, 1095–1114 (2024).

    Google Scholar 

  63. Costa-Mattioli, M. & Walter, P. The integrated stress response: from mechanism to disease. Science. 368, (2020).

  64. Nakagawa, T. & Ohta, K. Quercetin regulates the integrated stress response to improve memory. Int. J. Mol. Sci. 20, (2019).

  65. Duan, Y. A. et al. Interrelationship between platelets and BUN in postmenopausal patients with coronary heart disease: findings of the NHANES from 2003 to 2016. Eur. Rev. Med. Pharmacol. Sci. 28, 327–335 (2024).

    Google Scholar 

  66. Wu, J. et al. MicroRNA-188 suppresses G1/S transition by targeting multiple cyclin/CDK complexes. Cell. Commun. Signal. 12, 66 (2014).

    Google Scholar 

  67. Qin, R. X. et al. Transcriptomic analysis reveals the potential biological mechanism of AIS and lung adenocarcinoma. Front. Neurol. 14, 1119160 (2023).

    Google Scholar 

  68. He, Q. et al. Smoking-induced CCNA2 expression promotes lung adenocarcinoma tumorigenesis by boosting AT2/AT2-like cell differentiation. Cancer Lett. 592, 216922 (2024).

    Google Scholar 

  69. Robles-Jimenez, L. E. et al. Worldwide traceability of antibiotic residues from livestock in wastewater and soil: A systematic review. Animals. 12, (2021).

  70. Tan, X. D., Luo, C. F. & Liang, S. Y. Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma. J. Chemother. 36, 662–674 (2024).

    Google Scholar 

  71. Willer, S. M. Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart. J. Physiol. 601, 3717–3737 (2023).

    Google Scholar 

  72. Olschewski, A. et al. TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications. Eur. Respir. J. 50, (2017).

  73. Gu, J. et al. Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 Blockade. Exp. Mol. Med. 57, 567–583 (2025).

    Google Scholar 

  74. Lin, G. et al. KCNK3 inhibits proliferation and glucose metabolism of lung adenocarcinoma via activation of AMPK-TXNIP pathway. Cell. Death Discov. 8, 360 (2022).

    Google Scholar 

  75. Smoot, B. et al. Potassium channel candidate genes predict the development of secondary lymphedema following breast cancer surgery. Nurs. Res. 66, 85–94 (2017).

    Google Scholar 

  76. Smith, J., Tho, L. M., Xu, N. & Gillespie, D. A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 108, 73–112 (2010).

    Google Scholar 

  77. AACR Project GENIE. Powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

    Google Scholar 

  78. Tan, Z. et al. CHEK1: a hub gene related to poor prognosis for lung adenocarcinoma. Biomark. Med. 16, 83–100 (2022).

    Google Scholar 

  79. Xu, C. et al. Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy. Cell. Rep. Med. 6, 102078 (2025).

    Google Scholar 

  80. Ward, N. P. Cys-regulation: oxidized CHK1 controls cross-compartment circuit of chemoresistance. Trends Cancer. 9, 700–702 (2023).

    Google Scholar 

  81. You, J., Wang, X., Wang, J., Yuan, B. & Zhang, Y. DDX59 promotes DNA replication in lung adenocarcinoma. Cell. Death Discov. 3, 16095 (2017).

    Google Scholar 

  82. Hapke, G., Yin, M. B. & Rustum, Y. M. Targeting molecular signals in chk1 pathways as a new approach for overcoming drug resistance. Cancer Metastasis Rev. 20, 109–115 (2001).

    Google Scholar 

  83. Jin, M. et al. Circ_0011292 knockdown mitigates progression and drug resistance in PTX-resistant non-small-cell lung cancer cells by regulating miR-433-3p/CHEK1 axis. Thorac. Cancer. 13, 1276–1288 (2022).

    Google Scholar 

  84. Yu, Y. et al. Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway. Free Radic Biol. Med. 112, 397–410 (2017).

    Google Scholar 

  85. Pei, J. et al. GPX3 and GSTT1 as biomarkers related to oxidative stress during renal ischemia reperfusion injuries and their relationship with immune infiltration. Front. Immunol. 14, 1136146 (2023).

    Google Scholar 

  86. An, B. C. et al. GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines. PLoS One. 13, e0204170 (2018).

    Google Scholar 

  87. Rais, A., Husain, A., Hasan, G. M. & Hassan M. I. A review on regulation of cell cycle by extracellular matrix. Int. J. Biol. Macromol. 232, 123426 (2023).

    Google Scholar 

  88. Chapman, K. B. & Wolfner, M. F. Determination of male-specific gene expression in drosophila accessory glands. Dev. Biol. 126, 195–202 (1988).

    Google Scholar 

  89. Bard, J. A. M. et al. Structure and function of the 26S proteasome. Annu. Rev. Biochem. 87, 697–724 (2018).

    Google Scholar 

  90. Solomon, H. et al. Post-translational regulation of p53 function through 20S proteasome-mediated cleavage. Cell. Death Differ. 24, 2187–2198 (2017).

    Google Scholar 

  91. Enenkel, C., Kang, R. W., Wilfling, F. & Ernst, O. P. Intracellular localization of the proteasome in response to stress conditions. J. Biol. Chem. 298, 102083 (2022).

    Google Scholar 

  92. Fan, W. et al. m(6)A-Modified SNRPA controls alternative splicing of ERCC1 exon 8 to induce cisplatin resistance in lung adenocarcinoma. Adv. Sci. (Weinh). 11, e2404609 (2024).

    Google Scholar 

  93. Kaiser, A. M. et al. p53 governs an AT1 differentiation programme in lung cancer suppression. Nature 619, 851–859 (2023).

    Google Scholar 

  94. Shah, R. et al. Polarization of THP-1-Derived human M0 to M1 macrophages exposed to flavored E-Liquids. Toxics. 13, (2025).

  95. Malik, J. A. & Agrewala, J. N. Morphine’s role in macrophage polarization: exploring M1 and M2 dynamics and disease susceptibility. J. Neuroimmunol. 400, 578534 (2025).

    Google Scholar 

  96. Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell. 35, 588–602e510 (2019).

    Google Scholar 

  97. Fang, X. et al. Multi-omics analysis identified macrophages as key contributors to sex-related differences in ulcerative colitis. Front. Immunol. 16, 1569271 (2025).

    Google Scholar 

  98. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Google Scholar 

  99. Xu, K. et al. B-cell signatures characterize the immune landscape and predict LUAD prognosis via the integration of scRNA-seq and bulk RNA-seq. Sci. Rep. 15, 5453 (2025).

    Google Scholar 

  100. Chen, C. et al. Isoliensinine exerts antitumor effects in lung adenocarcinoma by inhibiting APEX1-driven ROS production. Front. Pharmacol. 16, 1555802 (2025).

    Google Scholar 

  101. Shi, H. et al. KLF13 promotes ferroptosis and chemosensitivity in lung adenocarcinoma. BMC Biol. 23, 178 (2025).

    Google Scholar 

Download references