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Differential expressions of miR-27a-3p and miR-155-5p in GBM cells and biopsies have already been described as markers of tumor subtype and progression. We aimed to evaluate the cellular and molecular impacts of inhibiting these two overexpressed miRNAs in GBM cell lines. A172 cells were transfected with miR-27a-3p and miR-155-5p inhibitors, and the effects on cellular processes and the expression of malignancy-related genes were analyzed by flow cytometry and qPCR, respectively. Thus, several cellular characteristics in A172 cells were modulated; however, only the inhibition of miR-27a-3p resulted in apoptosis, reduced glucose uptake, and a decrease in mitochondrial membrane potential. Both inhibitors modulated metabolic and immunological targets, negatively regulating genes in the glycolysis pathway and modulating other metabolic pathways involving glutamine and fatty acids, for example. Additionally, it modulates the TGF-\u03b2 pathway, which can influence the GBM microenvironment due to its immunosuppressive role in advanced tumors. miR-27a-3p appears to be a pivotal factor in the functional duality of TGF-\u03b2 and its interaction with HIF1A in the hypoxic tumor environment, modulating SMAD partners or TGF-\u03b2 pathway inhibitors. Here, we demonstrate the importance of inhibiting overexpressed miRNAs, particularly miR-27a-3p, in modulating key pathways for tumor cell survival. The results of this work provide new insights into potential targets for immune-metabolic interactions in the TME and their implications for tumorigenesis, shedding light on new therapeutic approaches for GBM.<\/jats:p>","DOI":"10.3390\/ijms26178729","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Downregulation of miR-27a-3p Modulates TGF-\u03b2 Signaling and Dysregulates Metabolism in Glioblastoma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-5366","authenticated-orcid":false,"given":"Augusto Ferreira","family":"Weber","sequence":"first","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, 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Kehl","family":"Dias","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil"},{"name":"Laboratory of Cancer Immunobiochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vin\u00edcius Pierdon\u00e1","family":"Lima","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamires","family":"de Bona","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Immunobiochemistry, Department of Biochemistry, Institute of Basic Health Sciences, 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