Hepatocellular Carcinoma (HCC) is one of the most common and fatal types of liver cancer worldwide; in this sense, Diethylnitrosamine (DEN) has been established as a potent carcinogen affecting the development and progression of this disease. The present work focused on determining whether phosphodiesterase (PDE) enzymes, especially PDE5, may serve as targets in the therapeutic treatment of DEN-induced HCC. PDE5 inhibitors, widely used as therapeutic drugs for cardiovascular diseases and erectile dysfunction, have recently been found to be promising in preclinical cancer models through the modulation of key signaling pathways implicated in the progression of tumors, such as the cGMP-PKG, JNK, and MAPK pathways. These pathways are very important for cell proliferation, apoptosis and metastasis, and their dysregulation contributes to the aggressive nature of HCC. This study assessed the potential of PDE5 inhibitors to suppress proliferation, induce apoptosis, and alter the tumor microenvironment, thus potentially improving standard chemotherapy and immunotherapy interventions. By inhibiting certain PDE isoforms with these drugs, an anticancer response might occur as part of a complex mechanism that acts on both cancer cells and the microenvironment favorable for tumor growth. A preliminary review indicated that PDE inhibitors may be a promising therapeutic approach for overcoming some of the shortcomings of current treatments, particularly the development of resistance and the toxic effects of these treatments. Additional clinical investigations are necessary to determine the safety profile, appropriate amount of Osage, and long-term efficacy of these agents in the treatment of HCC, particularly in DEN-induced animal models. This study contributes to the expanding body of evidence supporting the use of PDE inhibitors in cancer treatment.