Carcinoma is a type of cancer originating from epithelial tissue that lines various organs and internal passageways in the body (such as the esophagus) as well as the skin. It is the most prevalent type of cancer and accounts for 80 to 90 % of all cancer diagnoses. Carcinomas can manifest as tumors in diverse locations, including the skin, lungs, liver, breasts, prostate, colon, kidneys, and pancreas (Fan et al., 2022[38]).

Typically, cancers are identified by their origin within the body; however, this is merely one aspect of cancer classification. Cancers can also be categorized based on the tissue type where the cells proliferate. For instance, carcinoma originates from epithelial tissue. Myeloma originates from cancerous plasma cells in the bone marrow. Leukemia develops in the blood-producing cells of the bone marrow. Lymphoma can also spread to organs of the lymphatic system, such as the spleen and lymph nodes. Sarcoma arises from various supportive and connective tissues, including muscles, bones, and cartilage. Cancer can manifest in diverse tissue types, resulting in a spectrum of mixed forms (NIH, 2024[80]).

Multiple types of cancer are grouped together as carcinomas. Numerous types of carcinomas are found in the human body (Parikh et al., 2018[84]). Adenocarcinoma originates from glandular epithelial cells that line various organs. It is widespread in several types of malignancies, such as prostate, breast, colorectal, and pancreatic tumors (Selves et al., 2018[94]). Renal cell carcinoma (RCC) is a kind of adenocarcinoma that accounts for approximately 85 % of all kidney malignancies. It specifically affects renal cells located within the kidneys (Barata and Rini, 2017[12]). HCC is an extremely prevalent kind of cancer that originates in the liver. It arises from hepatocytes (liver cells) and is classified as an adenocarcinoma (Greaves, 2012[42]). Basal cell carcinoma (BCC) arises in the basal cell layer of the epidermis. It is a common kind of skin carcinoma. Basal cell carcinoma (BCC) frequently manifests as a partially translucent protuberance on the skin, particularly in sun-exposed regions such as the face, head, neck, and arms. Its growth tends to be slow, and it rarely spreads to other parts of the body (Kasper et al., 2012[58]).

Carcinoma cells often invade nearby healthy tissues and can form secondary growths (metastases) far from the original tumor. Symptoms of carcinoma vary depending on the affected body part but generally include fatigue, skin lumps or thickening, and weight changes, also shown in Figure 1(Fig. 1). Treatment options include surgery, radiation and chemotherapy (Jiang et al., 2015[56]; Karakuş et al., 2018[57]). HCC is the most common type of liver cancer and usually develops in individuals with advanced liver disease, especially those with cirrhosis. Chronic infections caused by hepatitis B or C play a substantial role in the development of cirrhosis and can increase the likelihood of HCC (El-Serag, 2012[35]). HCC is responsible for more than 90 % of liver cancer cases worldwide and results in more than 750,000 deaths each year. This makes it the fifth most prevalent form of cancer and the third major trigger of cancer-related mortality (death) on a global scale. While breast, lung, and large intestine cancers are also significant, liver and lung cancers have the highest mortality rates (Davis et al., 2008[26]).

Approximately 75-85 % of primary liver malignancies originate from hepatocytes, which are the major cellular component of the liver (Llovet et al., 2021[73]). The liver lies beneath the ribcage on the right side of the abdominal cavity and performs more than 500 important functions, including nutrient metabolism, blood coagulant protein synthesis, bile production, and detoxification. Hepatocarcinogenesis, or the path to HCC, begins with genetic alterations in hepatocytes due to carcinogens and includes DNA interactions. Continuous exposure to chemicals such as phenobarbital enhances tumor growth while simultaneously inducing the proliferation of already genotypically transformed hepatocytes, hence producing hyperplastic nodules that eventually progress to fully blown HCC (Chidambaranathan-Reghupaty et al., 2021[24]). Chronic infections with hepatitis B and C, alcohol use, and nonalcoholic fatty liver disease (NAFLD) are the major causes of HCC. Due to its etiologic association with liver cancer, DEN is a nitrosamine that is frequently used in the study of HCC in laboratory settings. DNA damage and chronic inflammation coupled with oxidative stress due to exposure to DEN favor the formation of tumors in the liver, also shown in Figure 2(Fig. 2). Many additional molecular insights are needed to design treatments and preventive strategies.

Phosphodiesterase inhibitors are drugs that enhance the widening of blood vessels (vasodilation) and relaxing of smooth muscles in certain areas of the body, such as the heart, lungs, and genitals. These inhibitors function by inhibiting the degradation of cyclic adenosine monophosphate-cAMP and cyclic guanosine monophosphate-cGMP within cells. By doing so, they help regulate physiological processes and reduce calcium levels in cells. While they are well known for treating erectile dysfunction, they also have other applications related to the heart and circulatory system (Konstantinos and Petros, 2009[64]; Butrous, 2014[16]).

PDE inhibitors function by blocking phosphodiesterase enzymes, thereby preventing the breakdown of cAMP and cGMP, which are essential for regulating various physiological processes by reducing intracellular calcium levels. The cAMP and cGMP second messengers mediate numerous physiological processes, including cell proliferation, apoptosis, and differentiation. Abnormal expression or dysregulation of specific PDE isoforms is implicated in the pathogenesis of many cancers, including HCC. PDE5 has been previously associated with cancer through its regulation of the cGMP-PKG signaling pathway. These inhibitors are categorized based on the PDE subtype they target: PDE5 inhibitors are employed to alleviate erectile dysfunction and pulmonary hypertension by promoting smooth muscle relaxation and enhancing blood circulation; PDE4 inhibitors elevate cAMP levels and are effective for pulmonary diseases such as asthma and COPD by targeting the airways, skin, immune system, and brain. Nonspecific inhibitors affect all PDEs to varying extents (Keravis and Lugnier, 2012[60]; Ahmad et al., 2015[3]).

Currently, U.S. FDA-approved PDE inhibitors are used for treating heart failure and pulmonary hypertension and for treating peripheral artery disease and prophylaxis after surgery for thromboembolism (Sheng et al., 2022[95]).

Furthermore, in the case of HCC, PDE inhibitors are suggested to act as anticancer agents. The reasons for this difference included the overexpression of the tumor suppressor gene PDE7B, which contributes to slowing the growth and metastasis of HCC-induced tumors. However, PDE4D inhibition reportedly affects the proliferation of HCC cells. Thus, PDE inhibitors may be potential therapeutic targets for the treatment of HCC (Ragusa et al., 2021[87]; Du et al., 2024[31]).

Phosphodiesterase inhibitors work by obstructing particular enzymes, which stops the degradation of the intracellular second messenger's cyclic adenosine monophosphate-cAMP and cyclic guanosine monophosphate-cGMP. The inhibition of PDEs, primarily PDE5, has been shown to be effective in preclinical models of cancer by inhibiting important pathways, such as the MAPK and JNK pathways, that influence the growth and death of cancer cells and metastasis. Some inhibitors are selective and target a particular type of PDE, while others are nonselective and affect multiple PDEs to varying degrees, see also Table 1(Tab. 1) (References in Table 1: Ahmad et al., 2022[4]; Asif, 2012[7]; Ausó et al., 2021[9]; Francis, 2005[40]; Huang and Lie, 2013[52]; Kawamatawong, 2021[59]; Li et al., 2018[68]; Mokra and Mokry, 2021[78]; Morales-Garcia et al., 2011[79]; Reneerkens et al., 2009[88]; Vang et al., 2016[102]; Wu et al., 2021[105]; Zagorska et al., 2018[108]; Zheng and Zhou, 2023[109]; Zuo et al., 2019[113]).

PDE5 inhibitors are quite promising for the treatment of HCC and prostate cancer. These proteins achieve this by modulating the cGMP-PKG, MAPK, and JNK pathways. This process inhibits tumor growth, accelerates apoptosis, and alters the microenvironment around the tumor. Since PDE4 regulates both the function of immune cells and cellular proliferation, inhibiting PDE4 is a promising approach for treating inflammation-driven cancers. PDE7 and PDE8 are more recent targets of drugs that may be targeted specifically against liver cancer, especially in the context of hepatocellular carcinoma and immune-related pathways of cancer. Dysregulation of phosphodiesterase isoforms, especially of phosphodiesterase 5, is among the several key causes of tumor growth, and blockade of these enzymes has enormous potential as a disease treatment. PDE inhibitors are a novel class of anticancer agents that target pathways indispensable for ensuring the viability and metastasis of tumor cells. These agents can be used in combination with other treatments, especially in severe conditions such as HCC.

In vivo studies have demonstrated the efficacy of PDE inhibitors in regulating cancer progression using many tumor models in animals, including genetically engineered mice, xenograft models, and chemically generated cancer models. The impact of PDE inhibitors on tumor start and progression in genetically engineered mice models was examined concerning apoptosis regulation and cell cycle arrest. In xenograft models, in which human cancer cells are implanted in immunocompromised mice, PDE inhibitors, among them PDE5 inhibitors, such as sildenafil, have been shown to suppress the expansion of tumor bulk by inhibiting angiogenesis and by activating apoptosis (Simeonova and Huillard, 2014[97]). In chemically induced cancer models, PDE inhibitors showed considerable potential for reducing growth in tumors by modulating both cAMP/PKA and cGMP/PKG pathways. Generally, PDE inhibitors cause the inhibition of tumor growth through apoptosis induction and anti-angiogenesis. Their anticancer effects also relate to the increased intracellular levels of cAMP or cGMP, which activate cell cycle arrest and apoptosis pathways (Ivanina Foureau et al., 2024[55]).

In vitro investigations utilizing cancer cell lines provide significant understanding of the molecular pathways by which PDE inhibitors influence cancer cell dynamics, encompassing proliferation, apoptosis, and metastasis (Mohan Shankar et al., 2022[77]). These results indicate that PDE inhibitors can diminish cancer cell growth and enhance apoptosis by elevating cAMP or cGMP levels, thereby activating protein kinase pathways (PKA, PKG) (Li et al., 2024[69]) and modulating apoptotic markers such as caspase-3, caspase-9, BAX, and BAD (Olsson and Zhivotovsky, 2011[82]). Moreover, deletion and overexpression models have been employed to elucidate the function of various PDE isoforms in cancer progression, demonstrating that PDE inhibition can augment apoptosis and diminish tumor growth. Selective PDE inhibitors, exemplified by PDE5 inhibitors, directly inhibit individual isoforms and effectively impede cancer proliferation, but broad-spectrum inhibitors, such as theophylline, influence many PDE isoforms and offer more extensive tumor suppression (Savai et al., 2010[92]).

In addition, both in vivo and in vitro studies have been able to document considerable evidence regarding the anti-cancer efficacy of PDE inhibitors as presented in Table 2(Tab. 2) (References in Table 2: Al-Ostoot et al., 2021[5]; Chen and Pandolfi, 2018[21]; Cruz-Burgos et al., 2021[25]; Engeland, 2022[36]; Martin and Jiang, 2009[75]; Olsson and Zhivotovsky, 2011[82]; Onaciu et al., 2020[83]; Savari et al., 2013[92]; Pognan et al., 2023[86]; Wong et al., 2012[104]). PDE inhibitors emerge as a potential therapy in cancer treatment due to their ability to suppress tumor growth, induce apoptosis, and interfere with metastasis. Further research, especially with specific and non-specific PDE inhibitors, will be crucial to determine their particular mechanisms at the molecular level and in the scope of clinical use in cancer.

PDE inhibitors have recently attracted much attention in oncological research because they can modulate key signaling pathways that are involved in the development of cancer. Most of the studies on PDE inhibitors have been conducted in the context of HCC, but these drugs have been active in many other types of cancers. The following overview of findings from a variety of cancers precedes discussion of the possible extension of PDE inhibition into cancer therapy beyond HCC (Table 3(Tab. 3); References in Table 3: Cruz-Burgos et al., 2021[25]; Bagchi et al., 2025[10]; Bałan et al., 2017[11]; Black et al., 2008[13]; Domvri et al., 2017[30]; Haider et al., 2021[47]; Li et al., 2024[70]; Sun et al., 2014[98]; Vandenberghe et al., 2019[101]).

PDE5 inhibitors, including drugs such as sildenafil, tadalafil, and vardenafil, are widely recognized for their ability to treat erectile dysfunction and pulmonary hypertension by enhancing vasodilation to improve blood flow. These inhibitors have shown great promise as anticancer agents, especially through tumor growth inhibition. These enzymes work by inhibiting the breakdown of the secondary messenger cyclic guanosine monophosphate (cGMP). PDE5 drugs inhibit the degradation of cGMP, thereby increasing the intracellular level of cGMP, which further activates protein kinase G (PKG). Activating PKG blocks a cascade of phosphorylation that affects central signaling molecules, including MEKK1, JNK (c-Jun N-terminal kinase), and ERK (extracellular signal-regulated kinase). These molecules play essential roles in controlling cell processes such as proliferation, apoptosis, and metastasis, all of which are significantly related to the propagation of cancer. JNK and ERK are specifically associated with signaling pathways that regulate the cell cycle and apoptosis; therefore, their dysregulation is generally observed in neoplastic cells. The ability of PDE5 inhibitors to induce apoptosis and decrease the invasive and proliferative characteristics of tumor cells is related to the regulation of these pathways. They may also affect the tumor microenvironment, decreasing the likelihood of cancer proliferation and growth. This complex action places PDE5 inhibitors of great interest as repositioned anticancer drugs, especially for the treatment of cancers such as HCC (Gross, 2010[43]; Kim et al., 2024[61]).

Many studies have been performed on PDE inhibitors in DEN-induced models of HCC. According to our review, PDE5 inhibitors can inhibit tumor development, increase tumor apoptosis, and alter the tumor microenvironment. They specifically target oncogenic pathways such as the Wnt/β-catenin, cyclin D1, and ERK1/2 pathways. Moreover, they induce an immunological response against tumors by modifying the tumor environment.

Hepatocellular carcinoma induced by diethylnitrosamine is the most commonly used model in cancer research for understanding how liver cancer progresses and how it can be treated. The reason is that DEN causes DNA damage, oxidative stress, and chronic inflammation and is considered a potent hepatocarcinogen. In an animal model, this leads to the occurrence of tumors in the organ. Currently, scientists are investigating alternative therapeutic strategies for treating DEN-induced aggressive HCC, and among the drugs in question is the inhibition of PDE5. Injection of DEN at various dosages ranging from 10 to 90 mg/kg body weight into rats led to lifelong carcinogenesis in the rodents under study. Because DEN has a strong impact on the liver, this compound has been used frequently as an experimental model for studying the pathogenetic mechanisms that cause liver carcinomas to develop.

For most patients, HCC can be treated via surgical resection, liver transplantation, or systemic therapy in the form of sorafenib and lenvatinib. However, in addition to suboptimal survival, drug resistance and side effects often limit these treatments. Molecularly targeted therapies, including PD-1/PD-L1 inhibitors, have improved outcomes in some patients but still have drawbacks, such as immune-related adverse events. PDE inhibitors, of course, are PDE5 inhibitors and are only one group of drugs in this new family of medicines; PDE5 inhibitors have not been tested thoroughly for HCC management until now. To understand their probable impact, all three must be compared with the existing treatments for HCC, including surgeries, systemic treatments, new molecules and immunotherapies, as listed in Table 4(Tab. 4) (References in Table 4: Deng et al., 2022[27]; Kumar et al., 2023[67]; Massimi et al., 2019[76]; Shimamura et al., 2022[96]; Tao et al., 2023[99]; Zhu et al., 2017[112]).

PDE5 inhibitors could increase the effectiveness of existing HCC therapies by permitting additional immune cells into a tumor, thereby weakening the immune system's ability to suppress the tumor and restoring normal blood flow to the area surrounding the tumor. Combination therapy utilizing PDE5 inhibitors together with checkpoint inhibitors such as PD-1 inhibitors may prove useful in the treatment of advanced HCC (Guerra et al., 2023[44]).

Table 5(Tab. 5) (Reference in Table 5: Hou et al., 2020[51]) shows that increased immune cell infiltration and PDE5 inhibitors may enhance the infiltration of immune cells into tumors; hence, the immune system may work better by targeting more cancer cells.

Reduced Immune Suppression: These drugs are likely to reduce the immunosuppressive environment within the tumor, and thus, this intense response comes from the immune system.

Blood Vessel Normalization by PDE5 Inhibitors: Normalization of blood vessels in the tumor microenvironment helps improve the delivery of other therapeutic agents in concert with the efficacy of the drug.

Synergistic effects: Combining PDE5 inhibitors with checkpoint inhibitors, such as PD-1 inhibitors, may synergistically enhance treatment efficacy in patients with advanced HCC.

This approach is still under investigation, but it holds promise for enhancing the effectiveness of existing therapies and improving patient outcomes.

PDE inhibitors are candidates for the treatment of hepatocellular carcinoma because they are specific for a particular PDE. Molecular docking is an in silico approach to predict the best binding mode of a chemical substance, a so-called PDE inhibitor, to a specific protein, a so-called PDE isoform. Some of the isoforms of PDE that have been implicated in cancer progression show a high level of binding affinity to PDE inhibitors. Because of their strong binding affinity, PDE inhibitors can effectively target and inhibit these isoforms, which interferes with the processes that help cancer cells grow.

Binding sites: Docking studies outlining the active locations of PDE isoforms that can be targeted by inhibitors. It is a very critical interaction because it may lead to interference with enzyme function-a process that is usually upregulated in cancer cells.

Binding affinity: This parameter is a measure of the strength of the inhibitor-PDE isoform interaction. High binding affinities indicate strong interactions, which are required for effective blocking of enzyme activity.

Silico studies: Silico research is based on computer models used to predict the consequences of PDE inhibitors on cellular activities. These results suggest that PDE inhibitors might interfere with crucial signaling pathways involved in cell proliferation and apoptosis. Apoptosis is an important process in the initiation and development of cancer. Programmed cellular death is known as apoptosis. Cancerous cells often evade apoptosis, ensuring survival and rapid proliferation. PDE inhibitors can reverse the apoptotic process, killing cancer cells (Kumar et al., 2024[66]).

A molecular review of these studies revealed the promising therapeutic potential of PDE in HCC. PDE inhibitors could increase the effectiveness of modern therapies and increase patient recovery rates by affecting the molecular mechanisms that facilitate cancer growth.

In combination with other drugs, such as PD-1 inhibitors, PDE inhibitors enhance the effectiveness of combination therapy. Synergistic effects of these drugs are believed to result in an increase in total therapeutic efficacy due to amalgamation. In immunomodulation, PDE inhibitors can change the immune response so that the tumor microenvironment is improved for infiltration and activation of immune cells. This approach may be used to improve the body's ability to fight cancer.

Molecular docking and in silico analyses provide relevant information for the treatment of HCC via PDE inhibitors (Kumar et al., 2025[65]). These inhibitors might diminish the progression of cancer and increase life expectancy through binding to specific isoforms of PDE and altering important signaling pathways. One way to develop a more potent and better combination treatment may be PDE inhibitors in combination with alternative medicines, such as immune checkpoint inhibitors.

However, additional research is needed to establish the long-term safety and effectiveness of PDE inhibitors in the clinic. Studying more selective PDE inhibitors and combination therapies, such as immunotherapy and targeted molecular therapy, may also improve the treatment outcomes of patients with HCC. The areas for future research involve several crucial domains:

Long-term effects: This goal will be accomplished through extensive clinical trials with HCC patients to determine the long-term effects of PDE inhibitors. The side effects of these agents need to be monitored, after which the most appropriate dosage can be determined to ensure that therapeutic benefits are sustainable.

Development of selective PDE inhibitors: Design and synthesis of additional more selective PDE inhibitors that selectively target the relevant isoforms involved in HCC progression. The specificity of such inhibitors could be improved through rational design to decrease off-target effects and enhance patient outcomes.

Combination therapies: To explore whether PDE inhibitors, such as PD-1/PD-L1 inhibitors, can be combined with these immunotherapies to achieve synergistic effects. Research on whether PDE inhibitors can be used in combination with certain targeted molecular therapies for greater efficacy is needed.

Mechanistic studies: We conducted the most molecular and mechanistic studies related to how PDE inhibitors modulate molecular mechanisms leading to signaling pathways in HCC and identified potential biomarkers to predict the response of patients who would benefit from receiving PDE inhibitor-based therapies.

Personalized medicine: Patients can receive individually tailored treatment approaches based on the genetic and molecular profiles of the individual patient. Precision medicine methods are applied to personalized PDE inhibitor therapies.

These findings could lead to promising future directions for improving the outcome of HCC treatment, providing better prospects for more effective and tailored therapeutic modalities.

This review will emphasize the continually increasing importance of PDE inhibitors as a potential therapeutic agent in DEN-induced HCC. These agents modulate proliferation, apoptosis, and immune responses in tumors by interfering with these essential pathways in the cell, including cGMP-PKG, MAPK, and JNK.

PDE inhibitors show a great promise to induce apoptosis, restrict the growth of tumor, and change the composition of immune cells within the TME. Still, despite such a promising benefit, their clinical use remains limited by heterogeneous preclinical data, safety issues, and a limited number of mechanistic studies. So, careful clinical studies and detailed molecular tests are required to prove how well they work and to create treatment plans.

Current treatments for HCC are not so effective, and there is a dire need for new therapies. Therefore, PDE inhibitors appear to be an exciting option to improve treatment. Their investigation, whether as a standalone treatment or in combination with current immunotherapies and chemotherapeutics, may enhance survival prospects and quality of life for patients with this difficult malignancy. Further study is necessary to actualize genuine potential and address the unmet needs in the treatment of HCC.

Anil Kumar and Harpreet Singh (School of Pharmaceutical Sciences (Faculty of Pharmacy), IFTM University, Moradabad, Uttar Pradesh-244102, India; E-mail: harpreetproctor@rediffmail.com) contributed equally as corresponding author.