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Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP\u2010HIPPO, Wnt\u2010<jats:italic>\u03b2<\/jats:italic>\u2010catenin, and nuclear factor\u2010<jats:italic>\u03ba<\/jats:italic>B (NF\u2010<jats:italic>\u03ba<\/jats:italic>B); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator\u2010activated receptor gamma (PPAR<jats:italic>\u03b3<\/jats:italic>) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first\u2010 and second\u2010line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.<\/jats:p>","DOI":"10.1155\/2021\/8837811","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T20:31:27Z","timestamp":1614544287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7435-1861","authenticated-orcid":false,"given":"Marina","family":"Galicia-Moreno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-8088","authenticated-orcid":false,"given":"Jorge A","family":"Silva-Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5384-1140","authenticated-orcid":false,"given":"Silvia","family":"Lucano-Landeros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4640-7263","authenticated-orcid":false,"given":"Arturo","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8891-5317","authenticated-orcid":false,"given":"Hugo C","family":"Monroy-Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7101-9943","authenticated-orcid":false,"given":"Juan","family":"Armendariz-Borunda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"e_1_2_10_1_2","volume-title":"Projections of Mortality and Causes of Death, 2016 to 2060","author":"World Health Organization","year":"2020"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2015.08.014"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2019.01.004"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v5.i7.345"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4202"},{"key":"e_1_2_10_6_2","first-page":"1","article-title":"Animal models as a tool in hepatocellular carcinoma research: a Review","volume":"3","author":"Santos N. 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