{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:53:10Z","timestamp":1778237590569,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Liaoning Provincial Science and Technology Plan Joint Fund Projects","award":["2023-MSLH-378"],"award-info":[{"award-number":["2023-MSLH-378"]}]},{"name":"Open Fund of The Key Laboratory of Environmental Pollution Health Risk Assessment, Ministry of Ecology and Environment of the People\u2019s Republic of China","award":["KLEPHRA-2024-6"],"award-info":[{"award-number":["KLEPHRA-2024-6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Arsenic, a ubiquitous metalloid, is commonly found in surface waters; as well as serious human health issues, it also induces systemic diseases and carcinogenesis upon chronic exposure. To better understand how arsenic potentially alters the immune system, it is important to study its effects on macrophage polarization. Micro-RNA plays an epigenetic regulatory role in organisms. The miR-125 family regulates macrophage polarization and tumorigenesis, yet its role in arsenic-induced macrophage polarization remains unexplored. This study investigated the mechanism of sodium arsenite (NaAsO2)-driven macrophage polarization via miR-125a-5p. In vivo, rats exposed to 10 or 50 mg\/L NaAsO2 for 12 weeks exhibited elevated M2 markers (CD206, Arg1) and reduced M1 markers (iNOS, IL-1\u03b2, TNF-\u03b1) in liver and bladder tissues. In vitro, THP-1-derived macrophages treated with NaAsO2 (2\u20138 \u03bcM) for 48 h showed dose-dependent M2 polarization, marked by upregulated CD206, Arg1, and IL-10. Flow cytometry results show that the proportion of M2\/M1-type cells has increased significantly. Notably, NaAsO2 suppressed miR-125a-5p expression and elevated interferon regulatory factor 4 (IRF4), a predicted target of miR-125a-5p. Overexpression of miR-125a-5p reversed NaAsO2-induced M2 polarization by inhibiting IRF4, thereby reducing M2 markers and restoring M1-associated proteins. These findings reveal that NaAsO2 promotes M2 macrophage polarization through the miR-125a-5p\/IRF4 axis, highlighting a novel epigenetic mechanism in arsenic-associated tumor microenvironments and immune dysfunction. This study provides critical insights into targeting miR-125a-5p as a therapeutic strategy.<\/jats:p>","DOI":"10.3390\/biom15111630","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:02:42Z","timestamp":1763640162000},"page":"1630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The miR-125a-5p\/IRF4 Axis Mediates Sodium Arsenite-Induced M2 Macrophage Polarization"],"prefix":"10.3390","volume":"15","author":[{"given":"Yan","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Yao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyuan","family":"Tong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingzheng","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qilong","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Pollution Health Risk Assessment, Ministry of Ecology and Environment, South China Institute of Environmental Sciences, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2638-067X","authenticated-orcid":false,"given":"Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang 110122, China"},{"name":"Liaoning Key Laboratory of Environmental Health Damage Research and Assessment, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuhua","family":"Xi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China"},{"name":"Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China"},{"name":"Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1289\/ehp.9058","article-title":"Biomarkers of exposure: A case study with inorganic arsenic","volume":"114","author":"Hughes","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111577","DOI":"10.1016\/j.fct.2020.111577","article-title":"Effects of curcumin, D-pinitol alone or in combination in cytotoxicity induced by arsenic in PC12 cells","volume":"144","author":"Rahaman","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"djw099","DOI":"10.1093\/jnci\/djw099","article-title":"Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic","volume":"108","author":"Baris","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1111\/1346-8138.13993","article-title":"Case-control study of chronic low-level exposure of inorganic arsenic species and non-melanoma skin cancer","volume":"44","author":"Kim","year":"2017","journal-title":"J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173090","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, N., Liang, H., and Zen, K. (2014). Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00614"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/SHK.0000000000000604","article-title":"MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response","volume":"46","author":"Essandoh","year":"2016","journal-title":"Shock"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21816","DOI":"10.1074\/jbc.M111.327031","article-title":"Identifying functional microRNAs in macrophages with polarized phenotypes","volume":"287","author":"Graff","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1158\/0008-5472.CAN-15-2019","article-title":"Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages","volume":"76","author":"Zhao","year":"2016","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1189\/jlb.1211593","article-title":"MiRNA-125b regulates TNF-\u03b1 production in CD14+ neonatal monocytes via post-transcriptional regulation","volume":"92","author":"Huang","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5062","DOI":"10.4049\/jimmunol.1102001","article-title":"MicroRNA-125b potentiates macrophage activation","volume":"187","author":"Chaudhuri","year":"2011","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.canlet.2019.04.015","article-title":"MicroRNA-125 in immunity and cancer","volume":"454","author":"Wang","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113056","DOI":"10.1016\/j.intimp.2024.113056","article-title":"The role of macrophage polarization in rheumatoid arthritis and osteoarthritis: Pathogenesis and therapeutic strategies","volume":"142","author":"Chang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1194\/jlr.M050633","article-title":"Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice","volume":"55","author":"Babaev","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1161\/ATVBAHA.119.312802","article-title":"Macrophages in Atherosclerosis Regression","volume":"40","author":"Barrett","year":"2020","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, S., Yang, S., Chen, Y., Li, R., Han, S., Kamili, A., Wu, Y., and Zhang, W. (2022). Ginsenoside Rb2 Alleviated Atherosclerosis by Inhibiting M1 Macrophages Polarization Induced by MicroRNA-216a. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.764130"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1742-4690-7-33","article-title":"The macrophage in HIV-1 infection: From activation to deactivation?","volume":"7","author":"Herbein","year":"2010","journal-title":"Retrovirology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4111","DOI":"10.1007\/s00018-015-1995-y","article-title":"Macrophage polarization in pathology","volume":"72","author":"Sica","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1089\/wound.2014.0568","article-title":"Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring","volume":"4","author":"Rees","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12967-020-02251-w","article-title":"Alternatively activated macrophages; a double-edged sword in allergic asthma","volume":"18","author":"Abdelaziz","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hesketh, M., Sahin, K.B., West, Z.E., and Murray, R.Z. (2017). Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071545"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"White, M.J., and Gomer, R.H. (2015). Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138748"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e37192","DOI":"10.1016\/j.heliyon.2024.e37192","article-title":"Shaping the immune landscape: Multidimensional environmental stimuli refine macrophage polarization and foster revolutionary approaches in tissue regeneration","volume":"10","author":"Xue","year":"2024","journal-title":"Heliyon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1097\/QCO.0000000000000550","article-title":"Metabolic immunomodulation of macrophage functional plasticity in nonhealing wounds","volume":"32","author":"Anders","year":"2019","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hung, C.H., Hsu, H.Y., Chiou, H.Y., Tsai, M.Y., You, H.Y., Lin, Y.C., Liao, W.T., and Lin, Y.C. (2022). Arsenic Induces M2 Macrophage Polarization and Shifts M1\/M2 Cytokine Production via Mitophagy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213879"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1756-8722-6-6","article-title":"Diverse functions of miR-125 family in different cell contexts","volume":"6","author":"Sun","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.imbio.2017.10.005","article-title":"The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2","volume":"223","author":"Chistiakov","year":"2018","journal-title":"Immunobiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e21615","DOI":"10.1016\/j.heliyon.2023.e21615","article-title":"The potential role of miRNA in regulating macrophage polarization","volume":"9","author":"Khayati","year":"2023","journal-title":"Heliyon"},{"key":"ref_30","first-page":"731023","article-title":"Interferon-regulatory factors determine macrophage phenotype polarization","volume":"2013","author":"Anders","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1073\/pnas.1914742117","article-title":"Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes","volume":"117","author":"Mamuna","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/jnc.15042","article-title":"MicroRNA-22-3p alleviates spinal cord ischemia\/reperfusion injury by modulating M2 macrophage polarization via IRF5","volume":"156","author":"Fang","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1007\/s10620-022-07679-2","article-title":"Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization","volume":"68","author":"Liang","year":"2023","journal-title":"Dig. Dis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1681\/ASN.2020071010","article-title":"Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation","volume":"32","author":"Sasaki","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Boutilier, A.J., and Elsawa, S.F. (2021). Macrophage Polarization States in the Tumor Microenvironment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136995"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pan, Y., Yu, Y., Wang, X., and Zhang, T. (2020). Tumor-Associated Macrophages in Tumor Immunity. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.583084"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.7150\/thno.51777","article-title":"Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages","volume":"11","author":"Chen","year":"2021","journal-title":"Theranostics"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1630\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:22:52Z","timestamp":1763641372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111630"],"URL":"https:\/\/doi.org\/10.3390\/biom15111630","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]}}}