{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T17:16:32Z","timestamp":1794071792302,"version":"4.8.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Siyang Hospital and the Affiliated Hospital of Jiangsu University in the first session of the hospital science and technology programmed projects to set up the topic","award":["2024SY005"],"award-info":[{"award-number":["2024SY005"]}]},{"name":"Siyang Hospital and the Affiliated Hospital of Jiangsu University in the first session of the hospital science and technology programmed projects to set up the topic","award":["2024SY005"],"award-info":[{"award-number":["2024SY005"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tuberculosis (TB), caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb), remains a major global public health threat. The rising prevalence of HIV\/TB co-infection and multidrug-resistant tuberculosis (MDR-TB) has further intensified this challenge. This study aims to explore the role of microRNAs (miRNAs) in the immune response to Mtb infection and to identify potential miRNA biomarkers for active TB diagnosis using machine learning techniques. miRNA expression profiles were retrieved from the Gene Expression Omnibus (GEO) database (accession number: GSE70425). Differential expression analysis between active TB and latent TB infection (LTBI) patients was conducted using the \u201climma\u201d package, with a screening threshold of |logFC| &gt; 0.25 and\n                    <jats:italic>p<\/jats:italic>\n                    -value\u2009&lt;\u20090.05. Key differentially expressed miRNAs (DE-miRNAs) were further refined using machine learning algorithms, including least absolute shrinkage and selection operator (LASSO) regression, support vector machine-recursive feature elimination (SVM-RFE), and Boruta. TargetScan was employed to predict miRNA target genes, and a regulatory network was visualized using Cytoscape. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to elucidate the functional roles of target mRNAs. Nine machine learning models were developed based on the selected miRNAs, and their predictive performance was assessed using metrics including AUROC, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In vitro experiments were performed using THP-1 macrophages to establish an Mtb infection model. Cells were transfected with miR-3607-3p mimics and negative controls, followed by flow cytometry for apoptosis detection, Western blot for protein expression analysis, and Quantitative Real-Time PCR (qRT-PCR) for validation of apoptosis-related gene expression. A total of 72 differentially expressed miRNAs were identified. Key miRNAs, including hsa-miR-3607-3p, hsa-miR-148b, and hsa-miR-519e, were identified through multiple machine learning methods, with hsa-miR-3607-3p emerging as the primary candidate miRNA. The nine machine learning models exhibited robust predictive performance in both the training and test sets. PPI network and functional enrichment analyses indicated that the target genes of hsa-miR-3607-3p are primarily associated with cell growth and apoptosis-related pathways. In vitro experiments further suggested that hsa-miR-3607-3p may modulate the apoptotic response of THP-1 cells to Mtb infection via a caspase-dependent mechanism. miR-3607-3p was upregulated in active TB patients and may modulate the apoptosis of THP-1 cells during Mtb infection via a caspase-dependent pathway. The mechanism of this miRNA offers preliminary insights into the immune regulation of tuberculosis. miR-3607-3p may serve as a potential biomarker for the early diagnosis and intervention of active TB; however, its clinical applicability necessitates further validation through larger sample sizes and multicenter studies.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-20112-8","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T10:20:39Z","timestamp":1760610039000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Machine learning identifies MiRNA biomarkers and immune mechanisms in active tuberculosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Zihan","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoupeng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"20112_CR1","unstructured":"World Health Organization. Global Tuberculosis Report 2024 (World Health Organization, Geneva,  2024)."},{"key":"20112_CR2","doi-asserted-by":"crossref","unstructured":"Murray, C. J. et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 399(10325), 629\u2013655 (2022).","DOI":"10.1016\/S0140-6736(21)02724-0"},{"issue":"10411","key":"20112_CR3","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1016\/S0140-6736(23)01379-X","volume":"402","author":"M Reid","year":"2023","unstructured":"Reid, M. et al. Scientific advances and the end of tuberculosis: A report from the lancet commission on tuberculosis. Lancet 402(10411), 1473\u20131498 (2023).","journal-title":"Lancet"},{"issue":"9907","key":"20112_CR4","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1016\/S0140-6736(13)62078-4","volume":"382","author":"A Zumla","year":"2013","unstructured":"Zumla, A. et al. WHO\u2019s 2013 global report on tuberculosis: successes, threats, and opportunities. Lancet 382(9907), 1765\u20131767 (2013).","journal-title":"Lancet"},{"issue":"1","key":"20112_CR5","doi-asserted-by":"publisher","first-page":"4295","DOI":"10.1038\/s41467-018-06836-4","volume":"9","author":"F Liu","year":"2018","unstructured":"Liu, F. et al. MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy. Nat. Commun. 9(1), 4295 (2018).","journal-title":"Nat. Commun."},{"issue":"8","key":"20112_CR6","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/s41423-022-00878-x","volume":"19","author":"Q Yao","year":"2022","unstructured":"Yao, Q. et al. Lnc-EST12, which is negatively regulated by mycobacterial EST12, suppresses antimycobacterial innate immunity through its interaction with FUBP3. Cell. Mol. Immunol. 19(8), 883\u2013897 (2022).","journal-title":"Cell. Mol. Immunol."},{"issue":"6","key":"20112_CR7","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1080\/15548627.2021.1987671","volume":"18","author":"Y Song","year":"2022","unstructured":"Song, Y. et al. Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival. Autophagy 18(6), 1401\u20131415 (2022).","journal-title":"Autophagy"},{"issue":"22","key":"20112_CR8","doi-asserted-by":"publisher","first-page":"3182","DOI":"10.1080\/15384101.2020.1838792","volume":"19","author":"G Liu","year":"2020","unstructured":"Liu, G. et al. Silencing miR-125b-5p attenuates inflammatory response and apoptosis inhibition in Mycobacterium tuberculosis-infected human macrophages by targeting DNA damage-regulated autophagy modulator 2 (DRAM2). Cell. Cycle 19(22), 3182\u20133194 (2020).","journal-title":"Cell. Cycle"},{"issue":"8","key":"20112_CR9","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1080\/15548627.2019.1582743","volume":"15","author":"TS Kim","year":"2019","unstructured":"Kim, T. S., Jin, Y. B., Kim, Y. S. et al. SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions. Autophagy 15(8), 1356\u20131375 (2019).","journal-title":"Autophagy"},{"issue":"1","key":"20112_CR10","doi-asserted-by":"publisher","first-page":"4246","DOI":"10.1038\/s41598-019-38982-0","volume":"9","author":"HS Park","year":"2019","unstructured":"Park, H. S. et al. Mycobacterium tuberculosis Rv3463 induces mycobactericidal activity in macrophages by enhancing phagolysosomal fusion and exhibits therapeutic potential. Sci. Rep. 9(1), 4246 (2019).","journal-title":"Sci. Rep."},{"key":"20112_CR11","doi-asserted-by":"publisher","first-page":"104203","DOI":"10.1016\/j.compbiomed.2020.104203","volume":"130","author":"M Jagadeb","year":"2021","unstructured":"Jagadeb, M. et al. Identification and evaluation of Immunogenic MHC-I and MHC-II binding peptides from Mycobacterium tuberculosis. Comput. Biol. Med. 130, 104203 (2021).","journal-title":"Comput. Biol. Med."},{"issue":"1","key":"20112_CR12","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1164\/rccm.202112-2747OC","volume":"206","author":"AN Buc\u015fan","year":"2022","unstructured":"Buc\u015fan, A. N., Veatch, A., Singh, D. K. et al. Response to hypoxia and the ensuing dysregulation of inflammation impacts Mycobacterium tuberculosis pathogenicity. Am. J. Respir Crit. Care Med. 206(1), 94\u2013104 (2022).","journal-title":"Am. J. Respir Crit. Care Med."},{"key":"20112_CR13","doi-asserted-by":"publisher","first-page":"1027472","DOI":"10.3389\/fimmu.2022.1027472","volume":"13","author":"L Wang","year":"2022","unstructured":"Wang, L. et al. MicroRNAs as immune regulators and biomarkers in tuberculosis. Front. Immunol. 13, 1027472 (2022).","journal-title":"Front. Immunol."},{"key":"20112_CR14","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.canlet.2018.05.028","volume":"431","author":"T Yang","year":"2018","unstructured":"Yang, T. & Ge, B. MiRNAs in immune responses to Mycobacterium tuberculosis infection. Cancer Lett. 431, 22\u201330 (2018).","journal-title":"Cancer Lett."},{"key":"20112_CR15","doi-asserted-by":"crossref","unstructured":"Hackett, E. E., Charles-Messance, H., O\u2019Leary, S. M. et al. Mycobacterium tuberculosis limits host glycolysis and IL-1\u03b2 by restriction of PFK-M via MicroRNA-21. Cell. Rep., 30(1), 124\u2013136 (2020).","DOI":"10.1016\/j.celrep.2019.12.015"},{"issue":"7031","key":"20112_CR16","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nature03441","volume":"434","author":"X Xie","year":"2005","unstructured":"Xie, X. et al. Systematic discovery of regulatory motifs in human promoters and 3\u2019 UTRs by comparison of several mammals. Nature 434(7031), 338\u2013345 (2005).","journal-title":"Nature"},{"issue":"6","key":"20112_CR17","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/ni.3434","volume":"17","author":"M Ouimet","year":"2016","unstructured":"Ouimet, M. & Koster, S. Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism. Nat. Immunol. 17(6), 677\u2013686 (2016).","journal-title":"Nat. Immunol."},{"issue":"2","key":"20112_CR18","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1080\/15548627.2016.1241922","volume":"13","author":"JK Kim","year":"2017","unstructured":"Kim, J. K. et al. MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. Autophagy 13 (2), 423\u2013441 (2017).","journal-title":"Autophagy"},{"issue":"1","key":"20112_CR19","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s10020-021-00296-1","volume":"27","author":"R Mirzaei","year":"2021","unstructured":"Mirzaei, R. et al. The emerging role of Exosomal MiRNAs as a diagnostic and therapeutic biomarker in Mycobacterium tuberculosis infection. Mol. Med. 27(1), 34 (2021).","journal-title":"Mol. Med."},{"key":"20112_CR20","doi-asserted-by":"crossref","unstructured":"Kim, J. et al. Identification of MicroRNAs as potential blood-based biomarkers for diagnosis and therapeutic monitoring of active tuberculosis. Diagnostics (Basel) 12(2), 369 (2022).","DOI":"10.3390\/diagnostics12020369"},{"issue":"46","key":"20112_CR21","doi-asserted-by":"publisher","first-page":"e27869","DOI":"10.1097\/MD.0000000000027869","volume":"100","author":"X Li","year":"2021","unstructured":"Li, X. et al. Diagnostic value of microRNA-155 in active tuberculosis: A systematic review and meta-analysis. Medicine (Baltimore) 100(46), e27869 (2021).","journal-title":"Medicine (Baltimore)"},{"issue":"D1","key":"20112_CR22","doi-asserted-by":"publisher","first-page":"D672","DOI":"10.1093\/nar\/gkae909","volume":"53","author":"M Kanehisa","year":"2025","unstructured":"Kanehisa, M. et al. KEGG: Biological systems database as a model of the real world. Nucleic Acids Res. 53(D1), D672\u2013D677 (2025).","journal-title":"Nucleic Acids Res."},{"key":"20112_CR23","doi-asserted-by":"crossref","unstructured":"Kanehisa, M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28(11), 1947\u20131951 (2019).","DOI":"10.1002\/pro.3715"},{"issue":"6","key":"20112_CR24","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.molmed.2020.02.001","volume":"26","author":"C Schulte","year":"2020","unstructured":"Schulte, C. et al. Noncoding RNAs versus protein biomarkers in cardiovascular disease. Trends Mol. Med. 26(6), 583\u2013596 (2020).","journal-title":"Trends Mol. Med."},{"key":"20112_CR25","doi-asserted-by":"crossref","unstructured":"Angria, N., Massi, M. N., Bukhari, A. et al. Expression of miRNA-29a-3p and IFN-\u03b3 as biomarkers in active and latent pulmonary tuberculosis. Ann. Med. Surg. (Lond). 83, 104786 (2022).","DOI":"10.1016\/j.amsu.2022.104786"},{"issue":"4","key":"20112_CR26","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1080\/13813455.2020.1752257","volume":"128","author":"M Mosallaei","year":"2022","unstructured":"Mosallaei, M. & Ehtesham, N. PBMCs: A new source of diagnostic and prognostic biomarkers. Arch. Physiol. Biochem. 128(4), 1081\u20131087 (2022).","journal-title":"Arch. Physiol. Biochem."},{"issue":"2","key":"20112_CR27","first-page":"629","volume":"9","author":"X Zhang","year":"2017","unstructured":"Zhang, X. et al. Down-regulation of hsa-miR-148b inhibits vascular smooth muscle cells proliferation and migration by directly targeting HSP90 in atherosclerosis. Am. J. Transl. Res. 9(2), 629\u2013637 (2017).","journal-title":"Am. J. Transl. Res."},{"key":"20112_CR28","doi-asserted-by":"crossref","unstructured":"Fayyad-Kazan, H., Bitar, N. et al. Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia. J. Transl. Med. 11, 31 (2013).","DOI":"10.1186\/1479-5876-11-31"},{"key":"20112_CR29","doi-asserted-by":"crossref","unstructured":"Jiang, X. & Chen, J. miR-150:targeting MLL leukemia. Oncotarget 3(11), 1268 (2012).","DOI":"10.18632\/oncotarget.736"},{"key":"20112_CR30","doi-asserted-by":"crossref","unstructured":"Ko, A. M. et al. ALPK1 genetic regulation and risk in relation to gout. Int. J. Epidemiol. 42(2), 466\u2013474 (2013).","DOI":"10.1093\/ije\/dyt028"},{"key":"20112_CR31","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.gene.2018.06.047","volume":"673","author":"Z He","year":"2018","unstructured":"He, Z. & Deng, W. Hsa-let-7b inhibits cell proliferation by targeting PLK1 in HCC. Gene 673, 46\u201355 (2018).","journal-title":"Gene"},{"issue":"1","key":"20112_CR32","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s12863-021-00997-w","volume":"22","author":"I Rooda","year":"2021","unstructured":"Rooda, I. et al. Hsa-mir-548 family expression in human reproductive tissues. BMC Genom Data. 22(1), 40 (2021).","journal-title":"BMC Genom Data"},{"issue":"4","key":"20112_CR33","doi-asserted-by":"publisher","first-page":"102363","DOI":"10.1016\/j.omtn.2024.102363","volume":"35","author":"S Kim","year":"2024","unstructured":"Kim, S. et al. miRNA-199b-5p suppresses of oral squamous cell carcinoma by targeting apical-basolateral Polarity via Scribble\/Lgl. Mol. Ther. Nucleic Acids. 35(4), 102363 (2024).","journal-title":"Mol. Ther. Nucleic Acids"},{"issue":"12","key":"20112_CR34","doi-asserted-by":"publisher","first-page":"e1007790","DOI":"10.1371\/journal.pgen.1007790","volume":"14","author":"P Gao","year":"2018","unstructured":"Gao, P. et al. miR-3607-3p suppresses non-small cell lung cancer (NSCLC) by targeting TGFBR1 and CCNE2. PLoS Genet. 14(12), e1007790 (2018).","journal-title":"PLoS Genet."},{"key":"20112_CR35","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.3389\/fimmu.2019.02819","volume":"10","author":"H Sun","year":"2019","unstructured":"Sun, H. et al. Natural killer cell-derived exosomal miR-3607-3p inhibits pancreatic cancer progression by targeting IL-26. Front. Immunol. 10, 2819 (2019).","journal-title":"Front. Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20112-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20112-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20112-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T10:20:51Z","timestamp":1760610051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20112-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["20112"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-20112-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"assertion":[{"value":"31 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study has been approved by the Ethics Committee of Siyang Hospital with the approval number HY2024005.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"36246"}}