Background: Hepatocellular carcinoma (HCC) is highly resistant to conventional therapies, highlighting the need for novel immunotherapeutic approaches. 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.