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In diabetic foot ulcers (DFUs), a persistent imbalance favoring pro\u2010inflammatory M1 over anti\u2010inflammatory M2 macrophages drives chronic inflammation and impedes tissue repair. This review delineates the central role of macrophage polarization in DFU pathogenesis and systematically summarizes the key signaling pathways that govern this process, including PI3K\/AKT, PPAR\u03b3, Notch, and Toll\u2010like receptors (TLRs). We further synthesize these cascades into a novel hierarchical network model, identifying NF\u2010\u03baB and JAK\u2013STAT as the core regulatory hubs. Beyond mechanism, we discuss emerging therapeutic strategies\u2014including pharmacological agents and biomaterial\u2010based approaches\u2014that target macrophage polarization, positioning them as promising adjuvants to standard wound care. By integrating mechanistic insights with therapeutic potential, this review provides an updated framework for developing targeted immunomodulatory therapies to break the cycle of non\u2010healing in DFUs.<\/jats:p>","DOI":"10.1111\/1753-0407.70205","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T01:59:57Z","timestamp":1773280797000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Insights Into Macrophage Polarization and\n                    <scp>M1<\/scp>\n                    \/\n                    <scp>M2<\/scp>\n                    Balance in Diabetic Foot Ulcers"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4270-8915","authenticated-orcid":false,"given":"Jing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Affiliated Hospital of Zunyi Medical University  Zunyi Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2181-2492","authenticated-orcid":false,"given":"Yulan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"Zunyi Medical University  Zunyi China"},{"name":"Department of Endocrinology and Metabolism Affiliated Hospital of Zunyi Medical University  Zunyi Guizhou China"},{"name":"Department of Endocrinology Kweichow Moutai Hospital  Renhuai Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1152-9"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2019.03.001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASW.0000416006.55218.d0"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1253836"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1586927"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12070"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2023.05.018"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601515"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2005.tb00337.x"},{"key":"e_1_2_10_11_1","first-page":"46","article-title":"MicroRNA as Therapeutic Targets for Chronic Wound Healing","volume":"8","author":"Mulholland E. 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