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In the tumor microenvironment (TME), the role of proinflammatory M1 macrophages remains ambiguous. The proteins Mapk4\/7 and cyclin E2 (CE2, Ccne2) are crucial for regulating hepatocyte proliferation and may be important factors driving the development of HCC. This study aimed to investigate the effects of M1 macrophages on CE2 and Mapk4\/7 expression, as well as hepatocyte proliferation, in a rat model of partial hepatectomy (PH) with or without diethylnitrosamine (DEN)-induced HCC. (2) Methods: Twenty female Wistar rats were assigned to nonneoplastic (PH) or neoplastic (PH\/DEN) groups. Gene expression (CE2, Mapk4\/7) was quantified via real-time PCR. (3) Results: Overexpression of CE2 and increased proliferation were observed in PH\/DEN hepatocytes, whereas exposure to proinflammatory M1 macrophages significantly reduced their proliferative activity. Mapk4\/7 expression patterns were modulated by the TME and significantly differ depending on macrophage activation status in both PH and PH\/DEN-derived hepatocytes. (4) Conclusions: Our findings indicate that CE2 expression is upregulated in PH\/DEN cells, with a notable decrease in the presence of M1 macrophages. In contrast, compared with control macrophages, M1 macrophages did not significantly affect Mapk4\/7 expression.<\/jats:p>","DOI":"10.3390\/molecules30173657","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T12:15:17Z","timestamp":1757420117000},"page":"3657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Impact of Proinflammatory M1 Macrophages on the Proliferation and Expression of Cyclin E2, Mitogen-Activated Protein Kinases 4 and 7 in Hepatocytes Isolated from a Diethylnitrosamine-Induced Hepatocellular Carcinoma Rat Model"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-1141","authenticated-orcid":false,"given":"Marta","family":"W\u00f3jcik","sequence":"first","affiliation":[{"name":"Oncology Lab, Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-612 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7530-7814","authenticated-orcid":false,"given":"Luisa","family":"Pozzo","sequence":"additional","affiliation":[{"name":"Institute of Agricultural Biology and Biotechnology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-2865","authenticated-orcid":false,"given":"Andrea","family":"Vornoli","sequence":"additional","affiliation":[{"name":"Institute of Agricultural Biology and Biotechnology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Longo","sequence":"additional","affiliation":[{"name":"Institute of Agricultural Biology and Biotechnology, National Research Council, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-4521","authenticated-orcid":false,"given":"Anna","family":"\u015amiech","sequence":"additional","affiliation":[{"name":"Department of Pathomorphology and Forensic Medicine, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-612 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2019-7819","authenticated-orcid":false,"given":"Joanna","family":"Czerwik-Marcinkowska","sequence":"additional","affiliation":[{"name":"Institute of Biology, Jan Kochanowski University, 25-369 Kielce, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona","family":"Rozempolska-Ruci\u0144ska","sequence":"additional","affiliation":[{"name":"Institute of Biological Basis of Animal Production, University of Life Sciences in Lublin, 20-950 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Chrapko","sequence":"additional","affiliation":[{"name":"Institute of Health Sciences, the J.P II Catholic University of Lublin, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon","family":"Zmorzynski","sequence":"additional","affiliation":[{"name":"Institute of Human Sciences, Faculty of Health Sciences, Academy of Zamosc, 22-400 Zamosc, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jhep.2019.08.025","article-title":"Epidemiology and Surveillance for Hepatocellular Carcinoma: New Trends","volume":"72","author":"Singal","year":"2020","journal-title":"J. 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