{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:43:33Z","timestamp":1781639013373,"version":"3.54.5"},"reference-count":67,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AIRC","award":["25187"],"award-info":[{"award-number":["25187"]}]},{"name":"AIRC","award":["PE_00000019"],"award-info":[{"award-number":["PE_00000019"]}]},{"name":"AIRC","award":["PRIN2022F8NS75"],"award-info":[{"award-number":["PRIN2022F8NS75"]}]},{"name":"AIRC","award":["DM 117\/2023"],"award-info":[{"award-number":["DM 117\/2023"]}]},{"name":"AIRC","award":["DM 352\/2022"],"award-info":[{"award-number":["DM 352\/2022"]}]},{"name":"European Union\u2014NextGenerationEU","award":["25187"],"award-info":[{"award-number":["25187"]}]},{"name":"European Union\u2014NextGenerationEU","award":["PE_00000019"],"award-info":[{"award-number":["PE_00000019"]}]},{"name":"European Union\u2014NextGenerationEU","award":["PRIN2022F8NS75"],"award-info":[{"award-number":["PRIN2022F8NS75"]}]},{"name":"European Union\u2014NextGenerationEU","award":["DM 117\/2023"],"award-info":[{"award-number":["DM 117\/2023"]}]},{"name":"European Union\u2014NextGenerationEU","award":["DM 352\/2022"],"award-info":[{"award-number":["DM 352\/2022"]}]},{"name":"Indena S.p.A. (Milano)","award":["25187"],"award-info":[{"award-number":["25187"]}]},{"name":"Indena S.p.A. (Milano)","award":["PE_00000019"],"award-info":[{"award-number":["PE_00000019"]}]},{"name":"Indena S.p.A. (Milano)","award":["PRIN2022F8NS75"],"award-info":[{"award-number":["PRIN2022F8NS75"]}]},{"name":"Indena S.p.A. (Milano)","award":["DM 117\/2023"],"award-info":[{"award-number":["DM 117\/2023"]}]},{"name":"Indena S.p.A. (Milano)","award":["DM 352\/2022"],"award-info":[{"award-number":["DM 352\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The approval of immunotherapy has revolutionized the management of hepatocellular carcinoma (HCC) patients. However, sorafenib remains a first-line therapeutic option for advanced patients and, in particular, for patients not eligible for immune checkpoint inhibitors, but its efficacy is limited by the onset of acquired resistance, highlighting the urgent need for predictive biomarkers. This study investigates the role of miR-22 in metabolic reprogramming and its potential as a biomarker in HCC. The analysis of miR-22 expression was performed in HCC patients and preclinical models by qPCR. Functional analyses in HCC cells evaluated GLUT1 as a direct miR-22 target. Cellular and metabolic assays evaluated the miR-22\/GLUT1 axis\u2019s role in metabolic changes, tumor aggressiveness, and sorafenib response. Circulating miR-22 was analyzed in sorafenib-treated HCC patients and rats. MiR-22 was downregulated in HCCs and associated with aggressive tumor features. Functionally, miR-22 modulated the HIF1A pathway, enhanced survival in stressful conditions, promoted a glycolytic shift, and enhanced cancer cell plasticity and sorafenib resistance via GLUT1 targeting. In addition, high serum miR-22 levels were associated with sorafenib resistance in HCC patients and rats. GLUT1 inhibition sensitized low miR-22-expressing HCC cells to sorafenib in preclinical models. These findings suggest that circulating miR-22 deserves attention as a predictive biomarker of sorafenib response. GLUT1 inhibition may represent a therapeutic strategy to combine with sorafenib, particularly in patients exhibiting high circulating miR-22 levels.<\/jats:p>","DOI":"10.3390\/ijms26083808","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T20:50:46Z","timestamp":1744923046000},"page":"3808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MiR-22\/GLUT1 Axis Induces Metabolic Reprogramming and Sorafenib Resistance in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Ilaria","family":"Leoni","sequence":"first","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"},{"name":"Centre for Applied Biomedical Research\u2014CRBA, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-9134","authenticated-orcid":false,"given":"Giuseppe","family":"Galvani","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"},{"name":"Centre for Applied Biomedical Research\u2014CRBA, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0679-6075","authenticated-orcid":false,"given":"Elisa","family":"Monti","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"},{"name":"Centre for Applied Biomedical Research\u2014CRBA, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Vianello","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"},{"name":"Centre for Applied Biomedical Research\u2014CRBA, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7266-7352","authenticated-orcid":false,"given":"Francesca","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Pincigher","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambra A.","family":"Grolla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5518-7214","authenticated-orcid":false,"given":"Marianna","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8362-6639","authenticated-orcid":false,"given":"Camelia A.","family":"Coada","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0905-2195","authenticated-orcid":false,"given":"Alessandro","family":"Perrone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2394-8462","authenticated-orcid":false,"given":"Valeria","family":"Righi","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7774-402X","authenticated-orcid":false,"given":"Gloria","family":"Ravegnini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1904-1577","authenticated-orcid":false,"given":"Catia","family":"Giovannini","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"},{"name":"Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7865-394X","authenticated-orcid":false,"given":"Maurizio","family":"Baldassarre","sequence":"additional","affiliation":[{"name":"Unit of Semiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Pariali","sequence":"additional","affiliation":[{"name":"U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5862-6151","authenticated-orcid":false,"given":"Matteo","family":"Ravaioli","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"},{"name":"Hepato-Biliary Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cescon","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"},{"name":"Hepato-Biliary Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-6025","authenticated-orcid":false,"given":"Francesco","family":"Vasuri","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"},{"name":"Pathology Unit, Santa Maria delle Croci Hospital, 40121 Ravenna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Domenicali","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Negrini","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, 44100 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-1845","authenticated-orcid":false,"given":"Fabio","family":"Piscaglia","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"},{"name":"Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8945-6826","authenticated-orcid":false,"given":"Romana","family":"Fato","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Stefanelli","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5187-9559","authenticated-orcid":false,"given":"Laura","family":"Gramantieri","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-5117","authenticated-orcid":false,"given":"Christian","family":"Bergamini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-4411","authenticated-orcid":false,"given":"Francesca","family":"Fornari","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy"},{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","article-title":"Global Trends in Hepatocellular Carcinoma Epidemiology: Implications for Screening, Prevention and Therapy","volume":"20","author":"Singal","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1200\/JCO.2022.40.4_suppl.379","article-title":"Phase 3 Randomized, Open-Label, Multicenter Study of Tremelimumab (T) and Durvalumab (D) as First-Line Therapy in Patients (Pts) with Unresectable Hepatocellular Carcinoma (uHCC): HIMALAYA","volume":"40","author":"Chan","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC Strategy for Prognosis Prediction and Treatment Recommendation: The 2022 Update","volume":"76","author":"Reig","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH Limits Anti-Tumour Surveillance in Immunotherapy-Treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1158\/1078-0432.CCR-18-2293","article-title":"Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies","volume":"25","author":"Harding","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.2147\/JHC.S268292","article-title":"MicroRNAs as Modulators of Tumor Metabolism, Microenvironment, and Immune Response in Hepatocellular Carcinoma","volume":"8","author":"Gramantieri","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1186\/s12967-023-04238-9","article-title":"The Interplay between Noncoding RNAs and Drug Resistance in Hepatocellular Carcinoma: The Big Impact of Little Things","volume":"21","author":"Fang","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12943-017-0751-3","article-title":"The Jun\/miR-22\/HuR Regulatory Axis Contributes to Tumourigenesis in Colorectal Cancer","volume":"17","author":"Liu","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_10","first-page":"1221","article-title":"MiR-22-3p Suppresses Cell Growth via MET\/STAT3 Signaling in Lung Cancer","volume":"13","author":"Yang","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41419-017-0206-1","article-title":"MiR-22 Suppresses Epithelial-Mesenchymal Transition in Bladder Cancer by Inhibiting Snail and MAPK1\/Slug\/Vimentin Feedback Loop","volume":"9","author":"Xu","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.7150\/thno.22493","article-title":"Identification and Functional Characterization of Long Non-Coding RNA MIR22HG as a Tumor Suppressor for Hepatocellular Carcinoma","volume":"8","author":"Zhang","year":"2018","journal-title":"Theranostics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.omtn.2021.10.003","article-title":"Suppression of Endothelial miR-22 Mediates Non-Small Cell Lung Cancer Cell-Induced Angiogenesis","volume":"26","author":"Gu","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1016\/j.ymthe.2023.04.019","article-title":"miR-22 Gene Therapy Treats HCC by Promoting Anti-Tumor Immunity and Enhancing Metabolism","volume":"31","author":"Hu","year":"2023","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yamakuchi, M., Yagi, S., Ito, T., and Lowenstein, C.J. (2011). MicroRNA-22 Regulates Hypoxia Signaling in Colon Cancer Cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020291"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cui, S., Chen, Y., Guo, Y., Wang, X., and Chen, D. (2023). Hsa-miR-22-3p Inhibits Liver Cancer Cell EMT and Cell Migration\/Invasion by Indirectly Regulating SPRY2. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0281536"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44252","DOI":"10.18632\/oncotarget.10020","article-title":"miR-22 Inhibits Tumor Growth and Metastasis by Targeting ATP Citrate Lyase: Evidence in Osteosarcoma, Prostate Cancer, Cervical Cancer and Lung Cancer","volume":"7","author":"Xin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/s41419-019-2127-7","article-title":"CircRNA-ENO1 Promoted Glycolysis and Tumor Progression in Lung Adenocarcinoma through Upregulating Its Host Gene ENO1","volume":"10","author":"Zhou","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"32375","DOI":"10.18632\/oncotarget.8632","article-title":"Metabolic Reprogramming Identifies the Most Aggressive Lesions at Early Phases of Hepatic Carcinogenesis","volume":"7","author":"Kowalik","year":"2016","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2147\/JHC.S285726","article-title":"Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions","volume":"8","author":"Fornari","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40170-023-00310-6","article-title":"BMP4 Upregulates Glycogen Synthesis through the SMAD\/SLC2A1 (GLUT1) Signaling Axis in Hepatocellular Carcinoma (HCC) Cells","volume":"11","author":"Zhong","year":"2023","journal-title":"Cancer Metab."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Xia, S., Pan, Y., Liang, Y., Xu, J., and Cai, X. (2020). The Microenvironmental and Metabolic Aspects of Sorafenib Resistance in Hepatocellular Carcinoma. EBioMedicine, 51.","DOI":"10.1016\/j.ebiom.2019.102610"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1158\/0008-5472.CAN-19-0472","article-title":"MiR-30e-3p Influences Tumor Phenotype through MDM2\/TP53 Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma","volume":"80","author":"Gramantieri","year":"2020","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fornari, F., Gramantieri, L., Callegari, E., Shankaraiah, R.C., Piscaglia, F., Negrini, M., and Giovannini, C. (2019). MicroRNAs in Animal Models of HCC. Cancers, 11.","DOI":"10.3390\/cancers11121906"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.7150\/thno.30958","article-title":"Acidic Microenvironment Up-Regulates Exosomal miR-21 and miR-10b in Early-Stage Hepatocellular Carcinoma to Promote Cancer Cell Proliferation and Metastasis","volume":"9","author":"Tian","year":"2019","journal-title":"Theranostics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12943-015-0490-2","article-title":"PKM2 Promotes Tumor Angiogenesis by Regulating HIF-1\u03b1 through NF-\u03baB Activation","volume":"15","author":"Azoitei","year":"2016","journal-title":"Mol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1158\/1078-0432.CCR-07-4478","article-title":"Endoglin (CD105): A Marker of Tumor Vasculature and Potential Target for Therapy","volume":"14","author":"Dallas","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.7150\/jca.72161","article-title":"GLUT1 Regulates the Tumor Immune Microenvironment and Promotes Tumor Metastasis in Pancreatic Adenocarcinoma via ncRNA-Mediated Network","volume":"13","author":"Li","year":"2022","journal-title":"J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.canlet.2014.09.028","article-title":"miR-22 as a Prognostic Factor Targets Glucose Transporter Protein Type 1 in Breast Cancer","volume":"356","author":"Chen","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2457006","DOI":"10.1155\/2023\/2457006","article-title":"MicroRNA-22 Regulates the Pro-Inflammatory Responses and M1 Polarization of Macrophages by Targeting GLUT1 and 4-1BBL","volume":"2023","author":"Kang","year":"2023","journal-title":"J. Immunol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41568-021-00378-6","article-title":"Cancer Metabolism: Looking Forward","volume":"21","author":"Chandel","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gjorgjieva, M., Sobolewski, C., Ay, A.-S., Abegg, D., Correia de Sousa, M., Portius, D., Berthou, F., Fournier, M., Maeder, C., and Rantakari, P. (2020). Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040170"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1038\/onc.2015.333","article-title":"Systematic Integration of Molecular Profiles Identifies miR-22 as a Regulator of Lipid and Folate Metabolism in Breast Cancer Cells","volume":"35","author":"Koufaris","year":"2016","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.cmet.2018.08.020","article-title":"Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma","volume":"29","author":"Lally","year":"2019","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ciscato, F., Ferrone, L., Masgras, I., Laquatra, C., and Rasola, A. (2021). Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094716"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/s41467-017-02733-4","article-title":"Hexokinase-2 Depletion Inhibits Glycolysis and Induces Oxidative Phosphorylation in Hepatocellular Carcinoma and Sensitizes to Metformin","volume":"9","author":"DeWaal","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4317","DOI":"10.1200\/JCO.20.02672","article-title":"Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update","volume":"38","author":"Gordan","year":"2024","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_39","first-page":"926","article-title":"Mechanisms of Drug Resistance in HCC","volume":"79","author":"Ladd","year":"2024","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2016.11.023","article-title":"Blocking Preferential Glucose Uptake Sensitizes Liver Tumor-Initiating Cells to Glucose Restriction and Sorafenib Treatment","volume":"388","author":"Zhang","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_41","first-page":"106789","article-title":"Targeted Blocking of EGFR and GLUT1 by Compound H Reveals a New Strategy for Treatment of Triple-Negative Breast Cancer and Nasopharyngeal Carcinoma","volume":"198","author":"Wang","year":"2024","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yang, H., Zhang, M.-Z.-H., Sun, H.-W., Chai, Y.-T., Li, X., Jiang, Q., and Hou, J. (2021). A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.783194"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122894","DOI":"10.1016\/j.ijpharm.2023.122894","article-title":"GLUT1 Transporter-Facilitated Solid Lipid Nanoparticles Loaded with Anti-Cancer Therapeutics for Ovarian Cancer Targeting","volume":"637","author":"Jagdale","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2162160","DOI":"10.1080\/10717544.2022.2162160","article-title":"Nanomicelles for GLUT1-Targeting Hepatocellular Carcinoma Therapy Based on NADPH Depletion","volume":"30","author":"Zhang","year":"2023","journal-title":"Drug Deliv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature03688","article-title":"Rac1b and Reactive Oxygen Species Mediate MMP-3-Induced EMT and Genomic Instability","volume":"436","author":"Radisky","year":"2005","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13046-018-0768-5","article-title":"Serum miR-22 as Potential Non-Invasive Predictor of Poor Clinical Outcome in Newly Diagnosed, Uniformly Treated Patients with Diffuse Large B-Cell Lymphoma: An Explorative Pilot Study","volume":"37","author":"Marchesi","year":"2018","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/bjh.17734","article-title":"MiR-22, a Serum Predictor of Poor Outcome and Therapy Response in Diffuse Large B-Cell Lymphoma Patients","volume":"195","author":"Rinaldi","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15350","DOI":"10.18632\/oncotarget.24601","article-title":"Circulating miR-106b-3p, miR-101-3p and miR-1246 as Diagnostic Biomarkers of Hepatocellular Carcinoma","volume":"9","author":"Moshiri","year":"2018","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Vadla, G.P., Daghat, B., Patterson, N., Ahmad, V., Perez, G., Garcia, A., Manjunath, Y., Kaifi, J.T., Li, G., and Chabu, C.Y. (2022). Combining Plasma Extracellular Vesicle Let-7b-5p, miR-184 and Circulating miR-22-3p Levels for NSCLC Diagnosis and Drug Resistance Prediction. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-10598-x"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1007\/s00262-020-02782-7","article-title":"microRNA Expression Patterns in Tumor Infiltrating Lymphocytes Are Strongly Associated with Response to Adoptive Cell Transfer Therapy","volume":"70","author":"Greenberg","year":"2021","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_51","first-page":"2159","article-title":"MiR-22 Regulated T Cell Differentiation and Hepatocellular Carcinoma Growth by Directly Targeting Jarid2","volume":"11","author":"Zhang","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13046-023-02718-w","article-title":"MiR-494 Induces Metabolic Changes through G6pc Targeting and Modulates Sorafenib Response in Hepatocellular Carcinoma","volume":"42","author":"Bergamini","year":"2023","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Fornari, F., Ferracin, M., Trer\u00e8, D., Milazzo, M., Marinelli, S., Galassi, M., Venerandi, L., Pollutri, D., Patrizi, C., and Borghi, A. (2015). Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141448"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.1158\/1078-0432.CCR-16-1464","article-title":"In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3\u2013Mediated Apoptosis","volume":"23","author":"Fornari","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1158\/1541-7786.MCR-13-0312-T","article-title":"P53\/Mdm2 Feedback Loop Sustains miR-221 Expression and Dictates the Response to Anticancer Treatments in Hepatocellular Carcinoma","volume":"12","author":"Fornari","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Suarez-Arnedo, A., Torres Figueroa, F., Clavijo, C., Arbel\u00e1ez, P., Cruz, J.C., and Mu\u00f1oz-Camargo, C. (2020). An Image J Plugin for the High Throughput Image Analysis of in Vitro Scratch Wound Healing Assays. PLoS ONE, 15.","DOI":"10.1101\/2020.04.20.050831"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-017-0076-6","article-title":"The Epigenetically Regulated miR-494 Associates with Stem-Cell Phenotype and Induces Sorafenib Resistance in Hepatocellular Carcinoma","volume":"9","author":"Pollutri","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_58","unstructured":"R Core Team (2022, August 31). European Environment Agency. Available online: https:\/\/www.eea.europa.eu\/data-and-maps\/indicators\/oxygen-consuming-substances-in-rivers\/r-development-core-team-2006."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_60","unstructured":"Korotkevich, G., Sukhov, V., Budin, N., Shpak, B., Artyomov, M.N., and Sergushichev, A. (2021). Fast gene set enrichment analysis. bioRxiv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1111\/febs.15561","article-title":"Coenzyme Q biosynthesis inhibition induces HIF-1\u03b1 stabilization and metabolic switch toward glycolysis","volume":"288","author":"Liparulo","year":"2021","journal-title":"FEBS J."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Rizzardi, N., Liparulo, I., Antonelli, G., Orsini, F., Riva, A., Bergamini, C., and Fato, R. (2021). Coenzyme Q10 Phytosome Formulation Improves CoQ10 Bioavailability and Mitochondrial Functionality in Cultured Cells. Antioxidants, 10.","DOI":"10.3390\/antiox10060927"},{"key":"ref_65","first-page":"3195","article-title":"Ex vivo HR-MAS magnetic resonance spectroscopy of normal and malignant human renal tissues","volume":"27","author":"Righi","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmre.1999.1789","article-title":"Strategies for diagnosing and alleviating artifactual attenuation associated with large gradient pulses in PGSE NMR diffusion measurements","volume":"139","author":"Price","year":"1999","journal-title":"J. Magn. Reason."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/cmr.a.20068","article-title":"HR-MAS NMR spectroscopy in the characterization of human tissues: Application to healthy gastric mucosa","volume":"28A","author":"Schenetti","year":"2006","journal-title":"Concepts Magn. Reson. Part A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3808\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:31Z","timestamp":1760030191000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3808"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":67,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083808"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083808","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]}}}