{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:24:30Z","timestamp":1785911070151,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University-level Scientific Research Startup Fund of Suzhou Polytechnic University","award":["KY2025R053"],"award-info":[{"award-number":["KY2025R053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The exact pathogenesis of Alzheimer\u2019s disease (AD), a neurodegenerative disorder, remains unclear. Ferroptosis is a form of cell death characterized by intracellular iron accumulation, and has emerged as a potential contributor to the pathological cascade of AD. Therefore, this study aims to identify core genes that may function as reliable biomarkers for AD through an in-depth analysis of the genetic relationship between ferroptosis-related genes and AD. Methods: This study first obtained the gene expression profiles (GSE140831, GSE63060 and GSE63061 expression profiles). The GSE140831 dataset served as the discovery cohort, and the GSE63060 and GSE63061 datasets were used as independent validation cohorts. R language 4.4.1 was used for standardizing and identifying differentially expressed genes (DEGs) in AD patients in all datasets. Secondly, the ferroptosis-related genes were obtained. By integrating the ferroptosis-related genes, ferroptosis-related DEGs (FRDEGs) were detected. Then, the FRDEGs were verified and evaluated, and the biological functions of the core genes were analyzed. Finally, miRNAs interacting with these core FRDEGs were explored. Results: The study identified nine FRDEGs (ACVR1B, BRPF1, G6PD, KLHDC3, LAMP2, MTCH1, P4HB, PTPN6, RBMS1), which are potentially related and may serve as biomarkers for AD. All nine genes demonstrated statistically significant differential expression (up-regulation) in both independent validation cohorts and in the combined analysis (p &lt; 0.05). Although the area under the curve (AUC) values of these nine genes ranged from 0.61 to 0.71, indicating moderate discriminatory power, these findings suggest that they may be involved in pathways related to AD and are worthy of further investigation as potential auxiliary biomarkers. Finally, a network of hub FRDEGs-miRNAs interaction was constructed. There were 11 miRNAs that may regulate these hub FRDEGs simultaneously. Conclusions: This study showed the significant association of the identified FRDEGs with AD. Also, a core ferroptosis-related biomarker network for miRNAs regulation of AD was constructed. The specific regulatory mechanism is worthy of further investigation.<\/jats:p>","DOI":"10.3390\/genes17020224","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:13:15Z","timestamp":1770808395000},"page":"224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Core Ferroptosis-Related Biomarkers and miRNA Regulatory Networks in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"17","author":[{"given":"Wenjia","family":"Liu","sequence":"first","affiliation":[{"name":"School of Electronic Information Engineering, Suzhou Polytechnic University, Suzhou 215104, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Rao","sequence":"additional","affiliation":[{"name":"School of Electronics and Information, Hangzhou Dianzi University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5250-243X","authenticated-orcid":false,"given":"Liyang","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Electronics and Information, Hangzhou Dianzi University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"907","DOI":"10.3233\/JAD-201369","article-title":"The Potential Role of Ferroptosis in Alzheimer\u2019s Disease","volume":"80","author":"Zhang","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-981-32-9358-8_16","article-title":"Amyloid-\u03b2 and Tau at the Crossroads of Alzheimer\u2019s Disease","volume":"1184","author":"Gallardo","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S379","DOI":"10.3233\/JAD-179944","article-title":"Iron and Alzheimer\u2019s Disease: An Update on Emerging Mechanisms","volume":"64","author":"Lane","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.1007\/s12035-018-1403-3","article-title":"Ferroptosis and Its Role in Diverse Brain Diseases","volume":"56","author":"Weiland","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1007\/s00018-016-2194-1","article-title":"Mechanisms of ferroptosis","volume":"73","author":"Cao","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1111\/jcmm.13008","article-title":"Ferroptosis, a new form of cell death, and its relationships with tumourous diseases","volume":"21","author":"Yu","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3233\/JAD-2004-6209","article-title":"Lipid peroxidation and oxidative imbalance: Early functional events in Alzheimer\u2019s disease","volume":"6","author":"Sung","year":"2004","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1007\/s11064-007-9360-7","article-title":"Iron: The Redox-active center of oxidative stress in Alzheimer disease","volume":"32","author":"Castellani","year":"2007","journal-title":"Neurochem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.redox.2017.01.021","article-title":"Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration","volume":"12","author":"Hambright","year":"2017","journal-title":"Redox Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.redox.2017.11.001","article-title":"\u03b1-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice","volume":"14","author":"Zhang","year":"2018","journal-title":"Redox Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, K., Jiang, X., Wu, M., Cao, X., Bao, W., and Zhu, L.Q. (2021). Ferroptosis, a Potential Therapeutic Target in Alzheimer\u2019s Disease. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.704298"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yan, N., and Zhang, J. (2020). Iron Metabolism, Ferroptosis, and the Links with Alzheimer\u2019s Disease. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01443"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1089\/ars.2020.8134","article-title":"Preventive and Therapeutic Strategies in Alzheimer\u2019s Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis","volume":"34","author":"Perry","year":"2021","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e22830","DOI":"10.1002\/jbt.22830","article-title":"Ferroptosis: A potential therapeutic target for neurodegenerative diseases","volume":"35","author":"Vitalakumar","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_16","first-page":"457","article-title":"Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders","volume":"13","author":"Nachun","year":"2019","journal-title":"bioRxiv"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s13059-015-0750-x","article-title":"A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status","volume":"16","author":"Sood","year":"2015","journal-title":"Genome Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"baaa021","DOI":"10.1093\/database\/baaa021","article-title":"FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations","volume":"2020","author":"Zhou","year":"2020","journal-title":"Database"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1213\/ANE.0b013e31829ed28f","article-title":"Wilcoxon-Mann-Whitney test used for data that are not normally distributed","volume":"117","author":"Dexter","year":"2013","journal-title":"Anesth. Analg."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Robin, X., Turck, N., Hainard, A., Tiberti, N., Lisacek, F., Sanchez, J.C., and M\u00fcller, M. (2011). pROC: An open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-77"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"W234","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s13760-016-0666-6","article-title":"Glucose-6-phosphate dehydrogenase a novel hope on a blood-based diagnosis of Alzheimer\u2019s disease","volume":"117","author":"Evlice","year":"2017","journal-title":"Acta Neurol. Belg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"144231","DOI":"10.1016\/j.gene.2019.144231","article-title":"Molecular evolution of autophagy rate-limiting factor LAMP2 in placental mammals","volume":"727","author":"Jalali","year":"2020","journal-title":"Gene"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bai, F., Yu, K., Yang, Y., Zhang, Y., Ding, L., An, X., Feng, F., Sun, N., Fan, J., and Liu, L. (2022). Identification and validation of P4HB as a novel autophagy-related biomarker in diabetic nephropathy. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.965816"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109189","DOI":"10.1016\/j.abb.2022.109189","article-title":"The regulatory effects of PTPN6 on inflammatory process: Reports from mice to men","volume":"721","author":"Kiratikanon","year":"2022","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/glia.23968","article-title":"Deletion of Alzheimer\u2019s disease-associated CD33 results in an inflammatory human microglia phenotype","volume":"69","author":"Nozaki","year":"2021","journal-title":"Glia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.biopsych.2015.04.005","article-title":"Brain glutathione levels\u2014A novel biomarker for mild cognitive impairment and Alzheimer\u2019s disease","volume":"78","author":"Mandal","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/NEN.0b013e3181cb5af4","article-title":"Oxidative stress in the progression of Alzheimer disease in the frontal cortex","volume":"69","author":"Ansari","year":"2010","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14285","DOI":"10.1002\/jcb.29004","article-title":"Neuroprotection by glucose-6-phosphate dehydrogenase and the pentose phosphate pathway","volume":"120","author":"Tang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1523\/JNEUROSCI.5098-09.2010","article-title":"Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal viability","volume":"30","author":"Allaman","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13046-019-1164-5","article-title":"Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation","volume":"38","author":"Mele","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41418-019-0287-8","article-title":"Autophagy in endothelial cells and tumor angiogenesis","volume":"26","author":"Schaaf","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3233\/JAD-230347","article-title":"Circulating exosomes from Alzheimer\u2019s disease suppress VE-cadherin expression and induce barrier dysfunction in recipient brain microvascular endothelial cell","volume":"95","author":"Bei","year":"2023","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.bbi.2020.04.058","article-title":"Leishmania infantum infection reduces the amyloid \u03b242-stimulated NLRP3 inflammasome activation","volume":"88","author":"Saresella","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Derkow, K., R\u00f6ssling, R., Schipke, C., Kr\u00fcger, C., Bauer, J., F\u00e4hling, M., Stroux, A., Schott, E., Ruprecht, K., and Peters, O. (2018). Distinct expression of the neurotoxic microRNA family let-7 in the cerebrospinal fluid of patients with Alzheimer\u2019s disease. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200602"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3233\/JAD-2008-14103","article-title":"Identification of miRNA changes in Alzheimer\u2019s disease brain and CSF yields putative biomarkers and insights into disease pathways","volume":"14","author":"Cogswell","year":"2008","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/YPG.0000000000000303","article-title":"Evaluation of hsa-let-7d-5p, hsa-let-7g-5p and hsa-miR-15b-5p plasma levels in patients with Alzheimer\u2019s disease","volume":"32","author":"Poursaei","year":"2022","journal-title":"Psychiatr. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.3892\/etm.2017.4977","article-title":"Overexpression of let-7a increases neurotoxicity in a PC12 cell model of Alzheimer\u2019s disease via regulating autophagy","volume":"14","author":"Gu","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_44","first-page":"899","article-title":"Let-7c increases BACE2 expression by RNAa and decreases A\u03b2 production","volume":"14","author":"Liu","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.1007\/s12035-016-0088-8","article-title":"Plasma miR-34a-5p and miR-545-3p as Early Biomarkers of Alzheimer\u2019s Disease: Potential and Limitations","volume":"54","author":"Antonell","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.3892\/mmr.2020.11162","article-title":"Integrated analysis of miRNA and mRNA expression in the blood of patients with Alzheimer\u2019s disease","volume":"22","author":"Wang","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s12031-016-0815-7","article-title":"miR-98-5p Acts as a Target for Alzheimer\u2019s Disease by Regulating A\u03b2 Production Through Modulating SNX6 Expression","volume":"60","author":"Li","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8826","DOI":"10.1007\/s12035-018-1032-x","article-title":"MicroRNA Expression Levels Are Altered in the Cerebrospinal Fluid of Patients with Young-Onset Alzheimer\u2019s Disease","volume":"55","author":"McKeever","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.neuroscience.2020.02.044","article-title":"Profile of Pathogenic Proteins and MicroRNAs in Plasma-derived Extracellular Vesicles in Alzheimer\u2019s Disease: A Pilot Study","volume":"432","author":"Li","year":"2020","journal-title":"Neuroscience"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:30:34Z","timestamp":1770809434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["genes17020224"],"URL":"https:\/\/doi.org\/10.3390\/genes17020224","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}