{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:17:05Z","timestamp":1788412625692,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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>Cuproptosis is a novel form of metabolism-associated cell death. Cervical cancer (CC) exhibits elevated serum copper levels and mitochondrial metabolic reprogramming, making cuproptosis-related genes (CRGs) potentially critical for prognosis prediction and therapeutic targeting. However, studies on CRGs in CC remain limited. This study aimed to construct prognostic and cancer staging models for CC using machine learning (ML) algorithms. Gene expression profiles of patients with CC were obtained from the TCGA and GEO databases. Five ML algorithms were employed to identify significant factors, including random forest (RF), support vector machine (SVM), Gaussian mixture model (GMM), Bayesian, and StepCox. A prognostic model was subsequently constructed using LASSO\u2013Cox regression based on the selected genes. Concurrently, a cancer staging model was built using ML algorithms incorporating three distinct gene categories. Finally, qRT-PCR and Western blotting were conducted to validate the expression of signature genes at both the tissue and cellular levels. Additionally, CTD-based screening and in vitro functional assays were performed to evaluate the effects of DDP on CC cells. Through integrated bioinformatics and ML approaches, a prognostic model comprising nine CRGs was successfully established (GMM = 0.72). The derived risk score served as an independent prognostic indicator for CC (p &lt; 0.001, 95% CI: 3.681 [1.785\u20137.591]). Calibration curves confirmed that the nomogram accurately predicted overall survival (OS) at 1, 3, and 5 years. Additionally, a cancer staging model was effectively constructed using the GMM algorithm (AUC = 0.74). DDP dose-dependently inhibited CC proliferation\/migration and down-regulated CRG expression. In this study, we developed two different models\u2014a cuproptosis-related prognostic model and a cancer staging model\u2014that highlight promising biomarkers for predicting patient prognosis and cancer progression in patients with CC.<\/jats:p>","DOI":"10.3390\/ijms27177730","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Analysis of Cuproptosis-Related Genes According to Cancer Stage and Their Prognostic Value in Cervical Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Jing","family":"He","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyan","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Clinical Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghua","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7231-1605","authenticated-orcid":false,"given":"Duo","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Clinical Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.soncn.2019.02.003","article-title":"Cervical Cancer: An Overview of Pathophysiology and Management","volume":"35","author":"Johnson","year":"2019","journal-title":"Semin. Oncol. Nurs."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"A10","DOI":"10.1016\/j.vaccine.2021.08.042","article-title":"National introduction of HPV vaccination in Senegal-Successes, challenges, and lessons learned","volume":"40","author":"Casey","year":"2022","journal-title":"Vaccine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12935-023-03189-x","article-title":"Identification of a new gene signature for prognostic evaluation in cervical cancer: Based on cuproptosis-associated angiogenesis and multi-omics analysis","volume":"24","author":"Kang","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Giannella, L., Di Giuseppe, J., Delli Carpini, G., Grelloni, C., Fichera, M., Sartini, G., Caimmi, S., Natalini, L., and Ciavattini, A. (2022). HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315022"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1177\/03008916231208344","article-title":"HPV-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: A focus on the potential role of vaccination","volume":"110","author":"Bogani","year":"2024","journal-title":"Tumori"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10697","DOI":"10.1038\/s41598-023-37898-0","article-title":"Identification of cuproptosis-related lncRNA for predicting prognosis and immunotherapeutic response in cervical cancer","volume":"13","author":"Kong","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e170223213775","DOI":"10.2174\/1874467216666230217151946","article-title":"Hsa_Circ_0000021 Sponges miR-3940-3p\/KPNA2 Expression to Promote Cervical Cancer Progression","volume":"17","author":"Zeng","year":"2024","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1200\/JCO.24.00440","article-title":"Sexual Health and Quality of Life in Patients With Low-Risk Early-Stage Cervical Cancer: Results from GCIG\/CCTG CX.5\/SHAPE Trial Comparing Simple Versus Radical Hysterectomy","volume":"43","author":"Ferguson","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa2308900","article-title":"Simple versus Radical Hysterectomy in Women with Low-Risk Cervical Cancer","volume":"390","author":"Plante","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.1200\/JCO.22.02852","article-title":"Randomized Phase III Study Comparing Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiation in Stage IB2-IIB Cervical Cancer: EORTC-55994","volume":"41","author":"Kenter","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105409","DOI":"10.1016\/j.compbiomed.2022.105409","article-title":"Colon cancer diagnosis and staging classification based on machine learning and bioinformatics analysis","volume":"145","author":"Su","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"273","DOI":"10.4103\/ijmr.IJMR_4225_20","article-title":"Implications of the revised cervical cancer FIGO staging system","volume":"154","author":"Bhatla","year":"2021","journal-title":"Indian J. Med. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1002\/1097-0142(19910601)67:11<2776::AID-CNCR2820671111>3.0.CO;2-L","article-title":"Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group","volume":"67","author":"Stehman","year":"1991","journal-title":"Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R421","DOI":"10.1016\/j.cub.2021.03.054","article-title":"Copper biology","volume":"31","author":"Tsang","year":"2021","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"161458","DOI":"10.1016\/j.scitotenv.2023.161458","article-title":"Cuproptosis is involved in copper-induced hepatotoxicity in chickens","volume":"866","author":"Zhong","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"216157","DOI":"10.1016\/j.canlet.2023.216157","article-title":"Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies","volume":"561","author":"Wang","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s10495-026-02266-6","article-title":"Harnessing Cuproptosis resistance to advance cancer therapeutics","volume":"31","author":"Li","year":"2026","journal-title":"Apoptosis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/s41423-022-00866-1","article-title":"Cuproptosis: A new form of programmed cell death","volume":"19","author":"Wang","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5359","DOI":"10.1016\/j.cell.2026.05.036","article-title":"Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance","volume":"189","author":"Lei","year":"2026","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1007\/s00011-023-01739-7","article-title":"Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics","volume":"72","author":"Xu","year":"2023","journal-title":"Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.3892\/ol.2012.655","article-title":"p16(INK4a) and p15(INK4b) gene promoter methylation in cervical cancer patients","volume":"3","author":"Jha","year":"2012","journal-title":"Oncol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12943-023-01732-y","article-title":"Cuproptosis: Mechanisms and links with cancers","volume":"22","author":"Xie","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, Y., and Zeng, X. (2022). A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1081952"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.cmi.2019.09.009","article-title":"Machine learning for clinical decision support in infectious diseases: A narrative review of current applications","volume":"26","author":"Rawson","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.3802\/jgo.2024.35.e17","article-title":"A machine learning-based prediction model of pelvic lymph node metastasis in women with early-stage cervical cancer","volume":"35","author":"Monthatip","year":"2024","journal-title":"J. Gynecol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1002\/cam4.4617","article-title":"Prediction of lung metastases in thyroid cancer using machine learning based on SEER database","volume":"11","author":"Liu","year":"2022","journal-title":"Cancer Med."},{"key":"ref_28","first-page":"41","article-title":"Applications of Support Vector Machine (SVM) Learning in Cancer Genomics","volume":"15","author":"Huang","year":"2018","journal-title":"Cancer Genom. Proteom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1152\/physiolgenomics.2000.4.2.109","article-title":"Analysis of molecular profile data using generative and discriminative methods","volume":"4","author":"Moler","year":"2000","journal-title":"Physiol. Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1007\/s13577-023-00914-6","article-title":"Role of cuproptosis in understanding diseases","volume":"36","author":"Cao","year":"2023","journal-title":"Hum. Cell"},{"key":"ref_31","first-page":"4074","article-title":"Pan-cancer profiles of the cuproptosis gene set","volume":"12","author":"Liu","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ferrari, F., and Giannini, A. (2024). Approaches to prevention of gynecological malignancies. BMC Women\u2019s Health, 24.","DOI":"10.1186\/s12905-024-03100-4"},{"key":"ref_33","first-page":"1289","article-title":"Regulation of Tumor Suppressor Gene CDKN2A and Encoded p16-INK4a Protein by Covalent Modifications","volume":"83","author":"Jiao","year":"2018","journal-title":"Biochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.tjog.2020.12.006","article-title":"A ceRNA network of BBOX1-AS1-hsa-miR-125b-5p\/hsa-miR-125a-5p-CDKN2A shows prognostic value in cervical cancer","volume":"60","author":"Wang","year":"2021","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1634\/theoncologist.2016-0310","article-title":"Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration","volume":"22","author":"Elvin","year":"2017","journal-title":"Oncologist"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1080\/1354750X.2019.1652685","article-title":"Clinical and prognostic effects of CDKN2A, CDKN2B and CDH13 promoter methylation in ovarian cancer: A study using meta-analysis and TCGA data","volume":"24","author":"Xia","year":"2019","journal-title":"Biomarkers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s12094-020-02409-4","article-title":"CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT\/mTOR pathway","volume":"23","author":"Luan","year":"2021","journal-title":"Clin. Transl. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e00398-20","DOI":"10.1128\/msphere.00398-20","article-title":"Transforming Properties of Beta-3 Human Papillomavirus E6 and E7 Proteins","volume":"5","author":"Minoni","year":"2020","journal-title":"mSphere"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"W\u0142oszek, E., Krupa, K., Skrok, E., Budzik, M.P., Depta\u0142a, A., and Badowska-Kozakiewicz, A. (2025). HPV and Cervical Cancer-Biology, Prevention, and Treatment Updates. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32030122"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Elsayim, R., Alhamdi, H.W., Almuraikhi, N., Alkhateeb, M.A., Derar, T.M.O., Mohamed, S.H.A., and Abudouleh, E. (2026). Multi-Omics Analysis of CDKN2A (p16INK4a) in Cervical Carcinoma in the Context of Human Papillomavirus and in Endometrial Carcinoma. Genes, 17.","DOI":"10.3390\/genes17030281"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.3802\/jgo.2023.34.e59","article-title":"AP2\u03b1 negatively regulates PDHA1 in cervical cancer cells to promote aggressive features and aerobic glycolysis in vitro and in vivo","volume":"34","author":"Zhao","year":"2023","journal-title":"J. Gynecol. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1832241","DOI":"10.1155\/2022\/1832241","article-title":"The Protective Mechanism of Afuresertib against Esophageal Cancer","volume":"2022","author":"Min","year":"2022","journal-title":"Dis. Markers"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ccell.2025.02.015","article-title":"Hypoxia inducible factor-1\u03b1 drives cancer resistance to cuproptosis","volume":"43","author":"Yang","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6142","DOI":"10.1111\/febs.15788","article-title":"Druggable genome and precision medicine in cancer: Current challenges","volume":"288","author":"Dupont","year":"2021","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/14656566.2023.2298329","article-title":"Pharmacotherapy for the treatment of recurrent cervical cancer: An update of the literature","volume":"25","author":"Bogani","year":"2024","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1177\/03008916211073621","article-title":"BYL719 (alpelisib) for the treatment of PIK3CA-mutated, recurrent\/advanced cervical cancer","volume":"109","author":"Bogani","year":"2023","journal-title":"Tumori"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.lungcan.2019.05.022","article-title":"Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer","volume":"135","author":"Noor","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"340","DOI":"10.21037\/tlcr.2019.08.22","article-title":"Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines","volume":"8","author":"Viteri","year":"2019","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1002\/ijc.31963","article-title":"Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma","volume":"144","author":"Augello","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9632","DOI":"10.1093\/nar\/gkac742","article-title":"Small-molecule activators specific to adenine base editors through blocking the canonical TGF-\u03b2 pathway","volume":"50","author":"Yang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nguyen, H.T., Theerakittayakorn, K., Somredngan, S., Ngernsoungnern, A., Ngernsoungnern, P., Sritangos, P., Ketudat-Cairns, M., Imsoonthornruksa, S., Assawachananont, J., and Keeratibharat, N. (2022). Signaling Pathways Impact on Induction of Corneal Epithelial-like Cells Derived from Human Wharton\u2019s Jelly Mesenchymal Stem Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063078"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41392-025-02192-0","article-title":"The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer","volume":"10","author":"Guo","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Zhang, W., Qu, H., Ma, X., Li, L., Wei, Y., Wang, Y., Zeng, R., Nie, Y., Zhang, C., and Yin, K. (2023). Identification of cuproptosis and immune-related gene prognostic signature in lung adenocarcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1179742"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Li, L., Li, L., and Sun, Q. (2022). High expression of cuproptosis-related SLC31A1 gene in relation to unfavorable outcome and deregulated immune cell infiltration in breast cancer: An analysis based on public databases. BMC Bioinform., 23.","DOI":"10.1186\/s12859-022-04894-6"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:46:44Z","timestamp":1788410804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":54,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177730"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177730","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}