{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T07:18:09Z","timestamp":1788247089653,"version":"build-2803163510"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010031","name":"Postdoctoral Research Foundation of China","doi-asserted-by":"publisher","award":["BSH036"],"award-info":[{"award-number":["BSH036"]}],"id":[{"id":"10.13039\/501100010031","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Diabetic foot ulcers (DFUs), a serious complication of diabetes, are associated with abnormal extracellular protein (EP) metabolism. The identification of key EPs and their regulatory networks is crucial for the understanding of DFU formation and development of effective treatments. In this study, a large-scale bioinformatics analysis was conducted to identify potential therapeutic targets and experimental validation was performed to ensure the reliability and biological relevance of the findings.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Due to the comprehensive profiling of DFU samples provided by the GSE80178 dataset, we initially selected it to derive differentially expressed genes (DEGs) associated with DFU. Subsequently, utilizing the UniProt database and annotated EP list from the Human Protein Atlas annotation database, we screened for extracellular protein\u2013related differentially expressed genes (EP-DEGs) due to their crucial role in the pathogenesis and healing of DFU. We examined EP-DEG pathway enrichment and protein-protein interaction networks, analyzed paired full-thickness skin tissue samples from 24 patients with DFUs and healthy controls, and performed polymerase chain reaction (PCR) experiments to validate candidate genes. Ultimately, we constructed a transcription factor (TF)-microRNA (miRNA)\u2013hub gene co-regulatory network to explore upstream and downstream regulatory connections based on validated DEGs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Four crucial candidate genes (FMOD, LUM, VCAN, and S100A12) were identified and verified via PCR analysis. The TF-miRNA-hub EP-DEG regulatory network contained the pivotal TFs TRIM28 and STAT3 and the miRNAs hsa-mir-20a-5p, hsa-miR-21, and hsa-miR-203.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The findings of this study advance our understanding of the pathology of DFU by defining key roles of specific EPs and elucidating a comprehensive regulatory network. These insights pave the way for novel approaches to improve DFU treatment outcomes.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0307205","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T17:30:19Z","timestamp":1721669419000},"page":"e0307205","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Key extracellular proteins and TF-miRNA co-regulatory network in diabetic foot ulcer: Bioinformatics and experimental insights"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6166-2800","authenticated-orcid":true,"given":"Guanlin","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9495-8820","authenticated-orcid":true,"given":"Ximing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"pone.0307205.ref001","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/S0140-6736(16)31679-8","article-title":"Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015.","volume":"388","author":"GBD 2015 Risk Factors Collaborators","year":"2016","journal-title":"Lancet Lond Engl"},{"key":"pone.0307205.ref002","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1056\/NEJMe1616575","article-title":"Increase in the Incidence of Diabetes and Its Implications","volume":"376","author":"JR Ingelfinger","year":"2017","journal-title":"N Engl J Med"},{"key":"pone.0307205.ref003","doi-asserted-by":"crossref","first-page":"14790","DOI":"10.1038\/s41598-020-71908-9","article-title":"Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025.","volume":"10","author":"X Lin","year":"2020","journal-title":"Sci Rep."},{"key":"pone.0307205.ref004","doi-asserted-by":"crossref","DOI":"10.2337\/db20182-1","volume-title":"Diagnosis and Management of Diabetic Foot Complications.","author":"AJM Boulton","year":"2018"},{"key":"pone.0307205.ref005","doi-asserted-by":"crossref","first-page":"102397","DOI":"10.1016\/j.dsx.2022.102397","article-title":"Prevalence and risk factors of lower limb amputations in patients with diabetic foot ulcers: A systematic review and meta-analysis","volume":"16","author":"BT Rodrigues","year":"2022","journal-title":"Diabetes Metab Syndr"},{"key":"pone.0307205.ref006","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/dom.14840","article-title":"Global mortality of diabetic foot ulcer: A systematic review and meta-analysis of observational studies","volume":"25","author":"L Chen","year":"2023","journal-title":"Diabetes Obes Metab"},{"key":"pone.0307205.ref007","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.3389\/fimmu.2018.01012","article-title":"Immune Modulation by Human Secreted RNases at the Extracellular Space.","volume":"9","author":"L Lu","year":"2018","journal-title":"Front Immunol."},{"key":"pone.0307205.ref008","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1177\/1534734607301394","article-title":"The extracellular matrix in wound healing: a closer look at therapeutics for chronic wounds","volume":"6","author":"MS Agren","year":"2007","journal-title":"Int J Low Extrem Wounds"},{"key":"pone.0307205.ref009","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/S0140-6736(05)67700-8","article-title":"Wound healing and its impairment in the diabetic foot","volume":"366","author":"V. 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