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Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg\/kg of diethylnitrosamine (DEN) and 25 mg\/kg of 2-Acetylaminofluorene (2-AAF). The HCC\/PFD group received simultaneous doses of 300 mg\/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, \u03b2-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPAR\u03b3 and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.<\/jats:p>","DOI":"10.3390\/cells13121013","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T08:49:03Z","timestamp":1718009343000},"page":"1013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pirfenidone Reverts Global DNA Hypomethylation, Promoting DNMT1\/UHRF\/PCNA Coupling Complex in Experimental Hepatocarcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Hipolito Otoniel","family":"Miranda-Roblero","sequence":"first","affiliation":[{"name":"Programa de Doctorado en Ciencias en Biolog\u00eda Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico"},{"name":"Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, 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Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Frias-Gonzalez","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Ciencias en Biolog\u00eda Molecular en Medicina, CUCS, University of Guadalajara, Guadalajara 44340, Mexico"},{"name":"Institute of Molecular Biology in Medicine and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara 44100, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Almeida-L\u00f3pez","sequence":"additional","affiliation":[{"name":"University Center of Health Sciences, University of Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Mart\u00ednez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Institute of Translational Nutrigenetics and Nutrigenomics, Department of Molecular Biology and 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