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The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.<\/jats:p>","DOI":"10.3390\/ijms22041794","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T18:45:00Z","timestamp":1613155500000},"page":"1794","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment"],"prefix":"10.3390","volume":"22","author":[{"given":"Mariam","family":"Mroweh","sequence":"first","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"},{"name":"Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath Beirut 6573-14, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5822-4320","authenticated-orcid":false,"given":"Ga\u00ebl","family":"Roth","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"},{"name":"Service D\u2019h\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0928-0048","authenticated-orcid":false,"given":"Thomas","family":"Decaens","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"},{"name":"Service D\u2019h\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8930-9340","authenticated-orcid":false,"given":"Patrice N.","family":"Marche","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8505-378X","authenticated-orcid":false,"given":"Herv\u00e9","family":"Lerat","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-5971","authenticated-orcid":false,"given":"Zuzana","family":"Macek J\u00edlkov\u00e1","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Universit\u00e9 Grenoble-Alpes, 38000 Grenoble, France"},{"name":"Service D\u2019h\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1001\/jamaoncol.2019.2996","article-title":"Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study","volume":"5","author":"Fitzmaurice","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.3748\/wjg.v25.i19.2279","article-title":"Mechanisms of hepatocellular carcinoma progression","volume":"25","author":"Ogunwobi","year":"2019","journal-title":"World J. 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