{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T11:33:31Z","timestamp":1786793611734,"version":"build-2736575974"},"reference-count":81,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32271154"],"award-info":[{"award-number":["32271154"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32571296"],"award-info":[{"award-number":["32571296"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32071115"],"award-info":[{"award-number":["32071115"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular diseases (CVDs), neurological disorders, digestive system diseases, respiratory conditions, and adipose-endocrine dysfunction. In cancer, miR-221 exerts context-dependent oncogenic\/tumor-suppressive effects by targeting phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 1c (CDKN1C\/p57), and BCL2 modifying factor (Bmf), thereby regulating cell proliferation, invasion, stemness, and resistance to cancer therapy; it also serves as a non-invasive biomarker for glioma, papillary thyroid carcinoma, and colorectal cancer. In the cardiovascular system, it balances antiviral defense in viral myocarditis, modulates ventricular fibrotic remodeling in heart failure, and regulates endothelial function in atherosclerosis, with cell-type\/ventricle-specific effects. In neurological disorders, it protects dopaminergic neurons in Parkinson\u2019s disease and modulates microglial activation in epilepsy. It also regulates hepatic pathogen defense and intestinal mucosal immunity. Mechanistically, miR-221 alters cellular phenotypes by targeting tumor suppressors or signaling components (e.g., PI3K\/AKT, TGF-\u03b2\/suppressor of mothers against decapentaplegic homolog(SMAD), Wnt\/\u03b2-catenin). Therapeutically, miR-221-targeting strategies show preclinical promise in cancer and CVDs. Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target.<\/jats:p>","DOI":"10.3390\/cells14231896","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T12:39:43Z","timestamp":1764679183000},"page":"1896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MicroRNA-221: A Context-Dependent Mediator in Human Diseases\u2014Highlights from Molecular Mechanisms to Clinical Translation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2280-8337","authenticated-orcid":false,"given":"Qiu-Xiao","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Experimental Teaching Center, College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Du","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyue","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping J.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0499-5661","authenticated-orcid":false,"given":"An-Jing","family":"Ren","sequence":"additional","affiliation":[{"name":"Experimental Teaching Center, College of Basic Medical Sciences, Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.1158\/0008-5472.CAN-15-0457","article-title":"Targeting the miR-221-222\/PUMA\/BAK\/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma","volume":"75","author":"Zhao","year":"2015","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, R., Qu, Y., Ji, Z., Hao, C., Su, Y., Yao, Y., Zuo, W., Chen, X., Yang, M., and Ma, G. 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