{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:58:15Z","timestamp":1790866695160,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Necroptosis is a regulated inflammatory form of programmed cell death mediated by RIPK1, RIPK3, and MLKL, but its clinical relevance in surgically resected non-small cell lung cancer (NSCLC) remains uncertain. This study evaluated the transcript-level expression of these genes and their associations with survival in 41 patients who underwent complete NSCLC resection without preoperative therapy. RNA was isolated from frozen tumor tissues, and mRNA expression was quantified using RT-qPCR. Expression was analyzed primarily as continuous log2(expression + 1)-transformed variables in Cox proportional hazards models; median-based groups were used only for exploratory Kaplan\u2013Meier visualization. The cohort comprised 34 males and 7 females, with a mean age of 61.0 years; 41.5% had adenocarcinoma and 58.5% had squamous cell carcinoma. The maximum follow-up was 145 months, and the 5-year overall survival rate was 46.3%. None of the three genes was significantly associated with overall or disease-free survival in either univariable or restricted adjusted Cox models. Median-based analyses similarly showed no significant survival differences. These findings do not support RIPK1, RIPK3, or MLKL transcript levels as standalone prognostic biomarkers in surgically resected NSCLC. Larger studies integrating transcriptomic, protein-level, and functional assessments are warranted.<\/jats:p>","DOI":"10.3390\/ijms27188361","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:23:56Z","timestamp":1790864636000},"page":"8361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcript-Level Expression Patterns of Necroptosis-Related Genes RIPK1, RIPK3, and MLKL in Surgically Resected Non-Small Cell Lung Cancer: An Exploratory Single-Center Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3383-4832","authenticated-orcid":false,"given":"Fatma Ilknur","family":"Ulugun","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Faculty of Medicine, Dokuz Eyl\u00fcl University, 35330Izmir, 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statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e32899","DOI":"10.1097\/MD.0000000000032899","article-title":"Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment","volume":"102","author":"Alduais","year":"2023","journal-title":"Medicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000487440","article-title":"Heterogeneity in lung cancer","volume":"85","author":"Carvalho","year":"2018","journal-title":"Pathobiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1183\/09059180.00003913","article-title":"Surgery for nonsmall cell lung cancer","volume":"22","year":"2013","journal-title":"Eur. Respir. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.7861\/clinmedicine.18-2-s41","article-title":"Recent advances in the management of lung cancer","volume":"18","author":"Jones","year":"2018","journal-title":"Clin. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Guo, H., Li, H., Zhu, L., Feng, J., Huang, X., and Baak, J.P.A. (2021). \u201cHow Long Have I Got?\u201d in stage IV NSCLC patients with at least 3 months up to 10 years survival, accuracy of long-, intermediate-, and short-term survival prediction is not good enough to answer this question. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.761042"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nchembio711","article-title":"Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury","volume":"1","author":"Degterev","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.semcancer.2022.07.007","article-title":"Necroptosis pathways in tumorigenesis","volume":"86","author":"Zhang","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113925","DOI":"10.1016\/j.biopha.2022.113925","article-title":"A glimpse of necroptosis and diseases","volume":"156","author":"Yang","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.trecan.2021.09.003","article-title":"Necroptosis and tumor progression","volume":"8","author":"Yan","year":"2022","journal-title":"Trends Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sprooten, J., De Wijngaert, P., Vanmeerbeerk, I., Martin, S., Vangheluwe, P., Schlenner, S., Krysko, D.V., Parys, J.B., Bultynck, G., and Vandenabeele, P. (2020). Necroptosis in immuno-oncology and cancer immunotherapy. Cells, 9.","DOI":"10.3390\/cells9081823"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2174\/0115665232340926241105064739","article-title":"The role of immunotherapy in lung cancer treatment: Current strategies, future directions, and insights into metastasis and immune microenvironment","volume":"25","author":"Li","year":"2025","journal-title":"Curr. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4908608","DOI":"10.1155\/2022\/4908608","article-title":"Necroptosis-related prognostic signature and nomogram model for predicting the overall survival of patients with lung cancer","volume":"2022","author":"Xuan","year":"2022","journal-title":"Genet. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhu, J., Wang, J., Wang, T., Zhou, H., Xu, M., Zha, J., Feng, C., Shen, Z., Jiang, Y., and Chen, J. (2022). Identification of molecular subtypes, risk signature, and immune landscape mediated by necroptosis-related genes in non-small cell lung cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.955186"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4698","DOI":"10.1111\/jcmm.17494","article-title":"Identification of necroptosis-related gene signature and characterization of tumor microenvironment infiltration in non-small-cell lung cancer","volume":"26","author":"Dai","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5503","DOI":"10.7150\/jca.46172","article-title":"Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer","volume":"11","author":"Park","year":"2020","journal-title":"J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1111\/1759-7714.15054","article-title":"Genetic variants in key necroptosis regulators predict the prognosis of non-small cell lung cancer after surgical resection","volume":"14","author":"Lee","year":"2023","journal-title":"Thorac. Cancer"},{"key":"ref_18","first-page":"e15665232357300","article-title":"Transcriptomic signatures in TP53 positive and negative tumor samples in NSCLC","volume":"26","author":"Xie","year":"2025","journal-title":"Curr. Gene Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"92","DOI":"10.2174\/0115665232292768240503050508","article-title":"Lipid-based nanocarriers for targeted gene delivery in lung cancer therapy: Exploring a novel therapeutic paradigm","volume":"25","author":"Beigi","year":"2025","journal-title":"Curr. Gene Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e210723218988","DOI":"10.2174\/1874467217666230721123554","article-title":"The mediating role of miR-451\/ETV4\/MMP13 signaling axis on epithelial\u2013mesenchymal transition in promoting non-small cell lung cancer progression","volume":"17","author":"Qian","year":"2024","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_21","first-page":"3830","article-title":"MLKL is a potential prognostic marker in gastric cancer","volume":"18","author":"Sun","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1002\/cncr.28144","article-title":"Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma","volume":"119","author":"Colbert","year":"2013","journal-title":"Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, B., Shi, D., Lv, X., Chen, S., Huang, Q., Xie, M., and Shao, Z. (2018). Prognostic and clinicopathological significance of MLKL expression in cancer patients: A meta-analysis. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4655-4"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21625","DOI":"10.1038\/s41598-024-72545-2","article-title":"Prognostic significance and response to immune checkpoint inhibitors of RIPK3, MLKL, and necroptosis in non-small cell lung cancer","volume":"14","author":"Duangthim","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12943-019-1029-8","article-title":"The role of necroptosis in cancer biology and therapy","volume":"18","author":"Gong","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e70015","DOI":"10.1002\/imm3.70015","article-title":"Immunometabolic features and key biomarkers in lung cancer complicated by pulmonary tuberculosis: Insights from transcriptome and clinical cohort analysis","volume":"1","author":"Yang","year":"2025","journal-title":"iMetaMed"},{"key":"ref_27","first-page":"62","article-title":"Breaking boundaries: Chronic diseases and the frontiers of immune microenvironments","volume":"1","author":"Li","year":"2025","journal-title":"Med Res."},{"key":"ref_28","first-page":"136","article-title":"Systematic investigation of tumor microenvironment and antitumor immunity with IOBR","volume":"1","author":"Fang","year":"2025","journal-title":"Med Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70070","DOI":"10.1002\/imt2.70070","article-title":"The microbiome in cancer","volume":"4","author":"Lin","year":"2025","journal-title":"iMeta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.cpan.2024.12.001","article-title":"Emerging trends and hot topics in the application of multi-omics in drug discovery: A bibliometric and visualized study","volume":"21","author":"Wang","year":"2024","journal-title":"Curr. Pharm. Anal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cpan.2024.12.002","article-title":"Advances in drug discovery based on network pharmacology and omics technology","volume":"21","author":"Liu","year":"2024","journal-title":"Curr. Pharm. Anal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jtho.2015.09.009","article-title":"The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer","volume":"11","author":"Goldstraw","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8361\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:30:40Z","timestamp":1790865040000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":33,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188361"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188361","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}