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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of hepatocellular carcinoma? ​

Abstract ​

Hepatocellular carcinoma (HCC) poses a significant global health challenge, being one of the most prevalent forms of liver cancer and a leading cause of cancer-related mortality. The etiology of HCC is multifactorial, primarily driven by chronic liver diseases such as viral hepatitis (HBV and HCV), alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). These conditions contribute to a hypercarcinogenic state characterized by chronic inflammation, oxidative stress, and genomic instability. Recent advances in molecular biology have revealed that genetic alterations, including mutations in key oncogenes and tumor suppressor genes, as well as epigenetic modifications, play critical roles in HCC development. Signaling pathways such as the PI3K/AKT/mTOR and WNT/β-catenin pathways are also implicated in the progression of HCC. Additionally, the tumor microenvironment, including interactions with hepatic stellate cells and immune cells, significantly influences tumor behavior and treatment responses. Current therapeutic strategies for HCC are limited, particularly for patients diagnosed at advanced stages, highlighting the need for novel approaches that target the underlying molecular mechanisms of the disease. Emerging therapies, including targeted treatments and immunotherapies, offer promise for improving patient outcomes. This review synthesizes current knowledge on the mechanisms of HCC, emphasizing the importance of understanding these pathways to develop effective prevention and treatment strategies.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Etiology and Risk Factors
    • 2.1 Chronic Viral Hepatitis
    • 2.2 Alcoholic and Non-Alcoholic Fatty Liver Disease
    • 2.3 Genetic Predisposition and Environmental Factors
  • 3 Molecular Mechanisms of HCC
    • 3.1 Genetic Alterations and Mutations
    • 3.2 Epigenetic Changes
    • 3.3 Signaling Pathways Involved in HCC
  • 4 Tumor Microenvironment
    • 4.1 Interaction with Hepatic Stellate Cells
    • 4.2 Role of Immune Cells
    • 4.3 Extracellular Matrix Remodeling
  • 5 Therapeutic Implications
    • 5.1 Current Treatment Strategies
    • 5.2 Emerging Therapies and Targeted Treatments
    • 5.3 Future Directions in HCC Research
  • 6 Conclusion

1 Introduction ​

Hepatocellular carcinoma (HCC) represents a significant global health challenge, being one of the most prevalent forms of liver cancer and a leading cause of cancer-related mortality worldwide. The complex etiology of HCC is multifactorial, involving a combination of genetic, epigenetic, and environmental influences. Chronic liver diseases, particularly those associated with viral hepatitis (such as hepatitis B and C) and alcoholic liver disease, are recognized as primary risk factors for the development of HCC [1][2]. Furthermore, the tumor microenvironment, which includes the interactions between cancer cells and surrounding stromal cells, plays a critical role in HCC pathogenesis [3]. Given the aggressive nature of HCC and its often late diagnosis, understanding the underlying mechanisms of its initiation and progression is vital for developing effective prevention and treatment strategies [4].

The significance of exploring HCC mechanisms cannot be overstated. With HCC's rising incidence, particularly in regions with high rates of viral hepatitis, there is an urgent need for enhanced diagnostic and therapeutic approaches. Current treatment options are limited, and most patients are diagnosed at advanced stages, leading to poor prognoses [5]. Advances in molecular biology have unveiled various genetic alterations, signaling pathways, and epigenetic changes that drive HCC [6]. Understanding these mechanisms is crucial not only for improving patient outcomes but also for identifying novel therapeutic targets [7].

Recent research has significantly advanced our knowledge of the molecular mechanisms involved in HCC. Genetic alterations, such as mutations in oncogenes and tumor suppressor genes, along with epigenetic modifications like DNA methylation and histone modifications, have been implicated in hepatocarcinogenesis [8][9]. Moreover, the role of signaling pathways, including the PI3K/AKT/mTOR and WNT/β-catenin pathways, has been highlighted as crucial in the progression of HCC [10]. Additionally, the interaction of HCC cells with the tumor microenvironment, including the involvement of immune cells and extracellular matrix remodeling, has emerged as a significant factor in tumor progression [3].

This review will systematically explore the multifaceted mechanisms contributing to HCC, structured as follows:

  1. Etiology and Risk Factors: This section will detail the major contributors to HCC, including chronic viral hepatitis, alcoholic and non-alcoholic fatty liver disease, and genetic predispositions [5].

  2. Molecular Mechanisms of HCC: We will discuss genetic alterations, epigenetic changes, and the signaling pathways involved in HCC development [4][10].

  3. Tumor Microenvironment: This section will highlight the interactions between HCC cells and the tumor microenvironment, focusing on the roles of hepatic stellate cells, immune cells, and extracellular matrix [3].

  4. Therapeutic Implications: We will review current treatment strategies, emerging therapies, and future directions in HCC research [5][11].

  5. Conclusion: Finally, we will summarize the key findings and discuss the implications for future research and clinical practice.

By synthesizing current knowledge on the mechanisms of HCC, this review aims to enhance our understanding of the biology of this aggressive malignancy and guide future studies aimed at combating HCC effectively. The insights gained will not only contribute to the scientific community's understanding of HCC but also potentially improve clinical outcomes for patients suffering from this devastating disease.

2 Etiology and Risk Factors ​

2.1 Chronic Viral Hepatitis ​

Hepatocellular carcinoma (HCC) is a complex malignancy primarily associated with chronic viral hepatitis, particularly infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). The pathogenesis of HCC in the context of chronic viral hepatitis involves multiple mechanisms that can be categorized into direct viral effects and indirect effects mediated by the host's immune response and inflammatory processes.

Chronic infection with HBV and HCV is a significant risk factor for HCC, as these viruses drive persistent liver inflammation and cellular dysregulation. The primary mechanisms through which HBV and HCV contribute to HCC include:

  1. Chronic Inflammation and Immune Response: Chronic hepatitis due to viral infections leads to ongoing inflammation, which promotes cellular damage and regeneration. This regenerative process can result in genomic instability and an increased risk of mutations, ultimately leading to malignant transformation of hepatocytes (Hino et al., 2002; Sukowati et al., 2016). The inflammatory environment is characterized by the secretion of cytokines and growth factors that can stimulate hepatocyte proliferation and fibrosis, creating a conducive environment for carcinogenesis (Park et al., 2007).

  2. Viral Integration and Genomic Instability: In the case of HBV, the virus can integrate its DNA into the host genome, disrupting normal cellular gene expression and leading to oncogenic changes. The HBx protein, a viral transactivator, plays a crucial role in this process by promoting cell growth and survival, and it is implicated in the development of HCC through its effects on various cellular signaling pathways (Park et al., 2007; Arzumanyan et al., 2013). In contrast, HCV does not integrate into the host genome but can still induce genomic instability through mechanisms such as oxidative stress and dysregulation of cellular signaling pathways (Tsai & Chung, 2010; D'souza et al., 2020).

  3. Oxidative Stress and Epigenetic Modifications: Both HBV and HCV infections are associated with increased oxidative stress, which can lead to DNA damage and mutations in hepatocytes. Additionally, chronic viral hepatitis can induce epigenetic changes, such as DNA methylation and histone modifications, that alter gene expression and contribute to the malignant phenotype (Zhao et al., 2021; Vescovo et al., 2016).

  4. Gut-Liver Axis and Microbiota Dysbiosis: The interplay between the gut microbiota and liver health is increasingly recognized as a factor in HCC development. Dysbiosis, or an imbalance in gut microbiota, can exacerbate liver inflammation and promote carcinogenesis through mechanisms involving the immune system and metabolic pathways (Stella et al., 2022).

  5. Cirrhosis and Fibrosis: The progression of chronic hepatitis to cirrhosis significantly increases the risk of HCC. Cirrhosis creates a fibrotic environment that is associated with altered blood flow, increased portal pressure, and a high turnover of hepatocytes, which further heightens the risk of malignant transformation (Capasso et al., 2024). The risk of developing HCC correlates with the degree of liver fibrosis, making regular surveillance crucial for early detection in at-risk populations (Stella et al., 2022).

In summary, the mechanisms underlying the development of HCC in the context of chronic viral hepatitis are multifaceted, involving a combination of direct viral effects, immune-mediated inflammation, oxidative stress, genomic instability, and epigenetic alterations. Understanding these mechanisms is critical for developing effective prevention and treatment strategies for HCC in patients with chronic viral hepatitis.

2.2 Alcoholic and Non-Alcoholic Fatty Liver Disease ​

Hepatocellular carcinoma (HCC) is a complex malignancy primarily associated with chronic liver diseases, including alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD). The etiology of HCC is multifactorial, with significant contributions from both alcoholic and non-alcoholic fatty liver diseases.

Alcoholic liver disease can lead to HCC through various mechanisms. Chronic alcohol consumption induces liver injury, leading to fatty liver, inflammation, and eventually cirrhosis. The carcinogenic processes are driven by the mutagenic effects of acetaldehyde, a toxic metabolite of alcohol, which forms adducts with proteins and DNA, causing genetic mutations. Additionally, alcohol consumption increases oxidative stress, which results in lipid peroxidation and inflammation, both of which contribute to the carcinogenic process. Alcohol also alters DNA methylation patterns and affects signaling pathways related to liver cancer progression [12].

On the other hand, NAFLD, which affects approximately one-fourth of individuals worldwide, has emerged as a significant risk factor for HCC, independent of cirrhosis. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) and ultimately to HCC involves several pathophysiological mechanisms. These include insulin resistance, chronic inflammation, and oxidative stress, which can lead to hepatocyte apoptosis and necrosis. Furthermore, the dysregulation of lipid metabolism and the accumulation of toxic lipid metabolites in the liver are implicated in the development of NASH and HCC [13].

The interplay between NAFLD and HCC is further complicated by the gut-liver axis, where alterations in gut microbiota can lead to increased intestinal permeability. This allows for the translocation of microbial products, which can exacerbate liver inflammation and promote carcinogenesis [14]. Additionally, the presence of obesity and type 2 diabetes, which are often associated with NAFLD, significantly heightens the risk of HCC due to their inflammatory and metabolic effects [15].

Recent studies have also highlighted the role of the tumor microenvironment in HCC development. Chronic liver inflammation, induced by both alcoholic and non-alcoholic fatty liver diseases, creates a pro-tumorigenic environment characterized by the activation of various signaling pathways, such as those involved in cell proliferation and survival [6]. The presence of immune cells, fibroblasts, and extracellular matrix components in the liver further supports tumor growth and progression [3].

In summary, the mechanisms of HCC associated with alcoholic and non-alcoholic fatty liver diseases involve a complex interplay of metabolic dysregulation, chronic inflammation, oxidative stress, genetic mutations, and alterations in the tumor microenvironment. Understanding these mechanisms is crucial for developing targeted prevention and treatment strategies for HCC.

2.3 Genetic Predisposition and Environmental Factors ​

Hepatocellular carcinoma (HCC) is a complex disease characterized by a multifactorial etiology that involves both genetic predisposition and environmental factors. The understanding of its mechanisms has evolved significantly, revealing the interplay between various risk factors, genetic alterations, and epigenetic changes.

The etiology of HCC is primarily linked to several major risk factors, including chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), which are prevalent globally and particularly in regions like Asia and Africa. These viral infections can lead to chronic hepatitis and cirrhosis, conditions that are present in 80-90% of HCC patients (Ding and Wang 2014) [16]. Additionally, lifestyle factors such as alcohol consumption, tobacco use, and metabolic disorders like nonalcoholic fatty liver disease contribute significantly to the development of HCC (Zhao et al. 2025) [17].

Genetic predisposition plays a crucial role in HCC development. The genetic landscape of HCC is marked by a high degree of heterogeneity, with numerous genetic alterations identified, including mutations in tumor suppressor genes such as p53, beta-catenin, and p16INK4A (Ozturk 1999) [18]. These mutations often result from environmental exposures, such as chemical carcinogens like aflatoxins, which can induce DNA damage and genomic instability. Moreover, there are rare monogenic syndromes associated with a heightened risk of HCC, though these are not commonly recognized outside specific regions (Dragani 2010) [19].

Epigenetic alterations also significantly influence HCC pathogenesis. Changes in DNA methylation patterns, histone modifications, and microRNA expression have been shown to contribute to the transformation of normal hepatocytes into malignant cells (Pogribny and Rusyn 2014) [1]. These epigenetic changes can be induced by environmental factors, thereby linking lifestyle and dietary habits to genetic expression profiles that favor carcinogenesis.

The interaction between genetic and environmental factors is critical in the progression of HCC. Chronic liver injury from viral hepatitis or alcohol consumption leads to a hypercarcinogenic state, characterized by increased cell proliferation and chromosomal instability (Hino et al. 2002) [20]. This environment fosters the accumulation of somatic mutations and epigenetic alterations, facilitating the transition from chronic liver disease to HCC.

In summary, the mechanisms underlying hepatocellular carcinoma are multifaceted, involving a combination of genetic predispositions and environmental risk factors. The interplay between these elements contributes to the initiation and progression of the disease, emphasizing the need for comprehensive strategies that address both genetic susceptibility and modifiable lifestyle factors in HCC prevention and management.

3 Molecular Mechanisms of HCC ​

3.1 Genetic Alterations and Mutations ​

Hepatocellular carcinoma (HCC) is characterized by a complex interplay of genetic alterations and mutations that contribute to its pathogenesis. The molecular mechanisms underlying HCC involve the accumulation of various genetic and epigenetic changes that drive tumor initiation, progression, and therapeutic resistance.

Genetic alterations in HCC include somatic mutations in key oncogenes and tumor suppressor genes. Notably, mutations in genes such as TP53, CTNNB1, and TERT have been identified as critical drivers of HCC. These mutations disrupt essential oncogenic pathways, influencing tumor behavior and response to treatment. For instance, TP53 mutations are frequently associated with a poor prognosis due to their role in cell cycle regulation and apoptosis [21]. Furthermore, genomic studies have revealed recurrent mutations and dysregulated signaling pathways that play significant roles in HCC development [4].

In addition to point mutations, HCC exhibits genomic instability, which can lead to chromosomal aberrations and the activation of oncogenes or inactivation of tumor suppressor genes. The involvement of various signaling pathways, including those related to telomere maintenance, Wnt/β-catenin signaling, and the P53 pathway, has been documented [22]. The genetic landscape of HCC is heterogeneous, indicating that different genetic alterations may be present in different subtypes of the disease [23].

Epigenetic modifications also play a crucial role in HCC pathogenesis. These alterations can influence gene expression without changing the underlying DNA sequence, leading to the activation of oncogenes and silencing of tumor suppressor genes. Common epigenetic changes observed in HCC include aberrant DNA methylation patterns, histone modifications, and alterations in non-coding RNAs such as microRNAs [24]. For example, DNA methylation changes can occur in both advanced tumors and premalignant conditions, highlighting their potential as early biomarkers for HCC [25].

Recent advances in high-throughput sequencing technologies have further elucidated the mutational landscape of HCC, allowing for the identification of novel driver mutations and epigenetic alterations that may serve as therapeutic targets [21]. The interplay between genetic and epigenetic changes contributes to the complexity of HCC, affecting not only tumor initiation and progression but also the response to targeted therapies [9].

Overall, the mechanisms of HCC involve a multifaceted network of genetic mutations and epigenetic alterations that together shape the tumor's behavior and clinical outcomes. Understanding these molecular mechanisms is essential for developing effective diagnostic and therapeutic strategies for HCC patients.

3.2 Epigenetic Changes ​

Hepatocellular carcinoma (HCC) is characterized by complex molecular mechanisms that involve significant epigenetic changes, contributing to its pathogenesis. The understanding of these mechanisms is crucial for developing effective therapeutic strategies.

Epigenetic alterations play a vital role in the initiation and progression of HCC. These alterations include changes in DNA methylation, histone modifications, and the expression of non-coding RNAs. Specifically, modified methylation patterns have been observed in HCC tumors, alongside dysfunction of enzymes responsible for DNA methylation, which significantly influences gene expression [24]. Histone modifications, particularly those affecting histone H3, also modulate transcriptional activities associated with tumorigenesis, affecting genes involved in various processes such as metabolism and metastasis [26].

Moreover, the epigenetic landscape in HCC is not static; it is reversible, providing potential therapeutic targets. This reversibility suggests that targeting these epigenetic modifications could be an effective strategy in HCC treatment. For instance, natural compounds like resveratrol and curcumin have shown promise in modulating epigenetic pathways associated with cancer [27].

The interplay between epigenetic changes and metabolic reprogramming is another critical aspect of HCC development. As metabolic dysfunction-associated steatotic liver disease (MASLD) has become a more prominent factor in HCC, understanding how epigenetic modifications interact with metabolic pathways is essential for elucidating the mechanisms of hepatocarcinogenesis [28]. Research indicates that abnormal epigenetic patterns are closely linked to metabolic alterations, suggesting a bidirectional relationship that could be exploited for therapeutic interventions [28].

Furthermore, the role of non-coding RNAs, including microRNAs and long non-coding RNAs, has been increasingly recognized in HCC. These molecules can regulate gene expression at the post-transcriptional level and are implicated in the dysregulation of key oncogenes and tumor suppressor genes during HCC development [24].

In summary, the molecular mechanisms of HCC are significantly influenced by epigenetic changes that encompass DNA methylation, histone modifications, and non-coding RNA dysregulation. These alterations not only contribute to the pathogenesis of HCC but also present novel avenues for targeted therapies aimed at reversing these changes to improve patient outcomes [9][24][27].

3.3 Signaling Pathways Involved in HCC ​

Hepatocellular carcinoma (HCC) is a complex malignancy characterized by various molecular mechanisms and signaling pathways that contribute to its initiation and progression. The pathogenesis of HCC involves alterations in several key signaling pathways, which can be categorized into multiple mechanisms.

  1. Receptor Tyrosine Kinase Pathways: These pathways play a significant role in HCC development. Dysregulation of receptor tyrosine kinases leads to increased cellular proliferation and survival, contributing to tumorigenesis. Targeting these pathways has emerged as a therapeutic strategy for HCC treatment (Dimri & Satyanarayana, 2020) [29].

  2. Ras/MAPK Pathway: The Ras/mitogen-activated protein kinase (MAPK) pathway is another critical pathway implicated in HCC. It is often activated due to mutations or other alterations, leading to enhanced cell growth and survival, further promoting hepatocarcinogenesis (Whittaker et al., 2010) [10].

  3. PI3K/AKT/mTOR Pathway: This pathway is frequently altered in HCC and is associated with cell growth, metabolism, and survival. The PI3K/AKT/mTOR signaling axis has been shown to be a vital target for therapeutic intervention, with various inhibitors being evaluated in clinical settings (Bang et al., 2023) [30].

  4. Wnt/β-Catenin Signaling: The Wnt/β-catenin pathway is frequently activated in HCC and is involved in various processes, including cell proliferation, differentiation, and survival. Aberrant activation of this pathway has been linked to the transition from chronic liver diseases to HCC and presents a promising target for novel therapies (Khalaf et al., 2018) [31].

  5. Hedgehog Signaling: Although less understood, the Hedgehog signaling pathway has been implicated in HCC. It is associated with cellular proliferation and survival, and its inhibition has shown potential in reducing HCC cell growth (Patil et al., 2006) [32].

  6. Apoptosis Signaling Pathways: Dysregulation of apoptosis is a hallmark of HCC, contributing to the malignant phenotype. Mechanisms that evade apoptosis involve alterations in cell death receptors and downstream signaling pathways, such as NF-κB and Bcl-2 family proteins. Understanding these pathways can provide insights into therapeutic resistance observed in HCC (Schattenberg et al., 2011) [33].

  7. Genetic Alterations: HCC is characterized by numerous genetic alterations, including mutations in oncogenes and tumor suppressor genes. These alterations affect multiple signaling pathways, leading to uncontrolled cell growth and tumor progression (Niu et al., 2016) [4].

  8. Emerging Molecular Targets: Recent research has focused on identifying new molecular targets for therapy, particularly those involved in the aberrant signaling pathways mentioned above. The understanding of these pathways is crucial for developing targeted therapies aimed at improving patient outcomes (Wang & Deng, 2023) [34].

In summary, the molecular mechanisms underlying HCC involve a complex interplay of various signaling pathways, including receptor tyrosine kinases, Ras/MAPK, PI3K/AKT/mTOR, Wnt/β-catenin, and Hedgehog signaling, along with significant genetic alterations. Targeting these pathways presents promising therapeutic opportunities for managing HCC effectively.

4 Tumor Microenvironment ​

4.1 Interaction with Hepatic Stellate Cells ​

Hepatocellular carcinoma (HCC) is significantly influenced by the tumor microenvironment (TME), which encompasses various cellular and non-cellular components. One of the critical cellular components of the HCC TME is hepatic stellate cells (HSCs). Activated HSCs play a pivotal role in the development and progression of HCC through multiple mechanisms.

Activated HSCs undergo transformation into myofibroblast-like cells, which promote fibrosis in response to liver injury or chronic inflammation. This fibrotic environment is conducive to the progression of cirrhosis and subsequently HCC. The TME is not only composed of activated HSCs but also includes tumor-associated macrophages (TAMs), endothelial cells, immune cells, and various extracellular matrix (ECM) proteins, all of which interact dynamically with HCC cells. These interactions can drive carcinogenesis and complicate therapeutic interventions aimed at HCC [35].

The role of HSCs in HCC is further elucidated by their capacity to secrete a variety of growth factors and cytokines, which contribute to the tumor-promoting microenvironment. For instance, HSCs can induce the expression of matrix metalloproteinases (MMPs) and other enzymes that facilitate the remodeling of the ECM, thus promoting tumor invasion and metastasis [36].

Recent studies have highlighted the epigenetic regulation of the HCC microenvironment, indicating that changes in DNA methylation, histone modifications, and non-coding RNA expression in HSCs and other TME components can significantly affect HCC development. This epigenetic modulation can alter the behavior of HSCs, leading to enhanced tumor growth and immune evasion [37].

Moreover, HSCs contribute to immune modulation within the TME. They can promote the development of myeloid-derived suppressor cells (MDSCs) through interleukin-6 (IL-6) signaling, which in turn suppresses T-cell activity and enhances tumor progression [38]. This immunosuppressive environment allows HCC cells to evade immune surveillance, thereby facilitating their growth and metastasis.

The interaction between HCC cells and activated HSCs also involves paracrine signaling mechanisms, where soluble factors secreted by HSCs can induce epithelial-mesenchymal transition (EMT) in tumor cells, further enhancing their invasive potential [39]. This EMT process is crucial for the transition of tumor cells from a stationary to a migratory state, which is a hallmark of cancer metastasis.

In summary, the mechanisms by which HSCs interact with the TME and contribute to HCC progression include promoting fibrosis, secreting growth factors and cytokines, mediating immune suppression, and facilitating EMT. Understanding these interactions offers potential therapeutic targets for HCC, as modulating the TME could improve treatment outcomes [40].

4.2 Role of Immune Cells ​

Hepatocellular carcinoma (HCC) is a complex malignancy characterized by its intricate tumor microenvironment (TME), which plays a pivotal role in its pathogenesis and progression. The TME of HCC is composed of various immune cells, fibroblasts, and extracellular matrix components, all of which interact dynamically with tumor cells. This microenvironment significantly influences tumor initiation, progression, and metastasis.

Immune cells within the TME of HCC can be categorized into innate and adaptive components. The innate immune component includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and natural killer T (NKT) cells. These cells can exhibit both pro-tumoral and anti-tumoral effects. For instance, tumor-associated macrophages (TAMs) can promote tumor growth and metastasis by stimulating angiogenesis, enhancing immunosuppression, and contributing to drug resistance [41]. Conversely, cytotoxic T lymphocytes (CTLs) and natural killer cells are generally involved in anti-tumor immunity, although their effectiveness can be hampered by the immunosuppressive nature of the TME [42].

Chronic inflammation is a significant driver of HCC, often resulting from viral hepatitis, alcohol abuse, or metabolic diseases. This inflammatory environment leads to the production of various cytokines and growth factors that promote tumorigenesis. The persistent inflammatory stimuli can cause cellular damage and lead to dysregulation of immune responses, facilitating the development of HCC [43]. Furthermore, chronic inflammation is associated with the activation of immune checkpoints, which further suppresses anti-tumor immune responses [44].

The TME is also characterized by an immunosuppressive milieu, where regulatory T cells (Tregs) and MDSCs play crucial roles in dampening effective immune responses against tumor cells. The recruitment and activation of these cells are mediated by various signaling pathways, including those activated by cancer-associated fibroblasts and other stromal cells [45].

Moreover, metabolic reprogramming of immune cells within the TME has been shown to significantly influence their function and the overall immune response in HCC. Changes in the metabolic state of immune cells can dictate their differentiation and activity, impacting tumor progression [46]. For instance, the shift towards a more glycolytic metabolism in tumor-infiltrating lymphocytes can impair their cytotoxic functions [42].

In summary, the immune cells within the TME of HCC play multifaceted roles that can either promote or inhibit tumor progression. The balance between pro-tumoral and anti-tumoral activities of these immune cells is critical in determining the overall outcome for patients with HCC. Understanding these mechanisms is essential for developing effective immunotherapeutic strategies aimed at reprogramming the TME to enhance anti-tumor immunity and improve patient outcomes.

4.3 Extracellular Matrix Remodeling ​

Hepatocellular carcinoma (HCC) is significantly influenced by the tumor microenvironment (TME), particularly through the remodeling of the extracellular matrix (ECM). The ECM serves as a critical component of the TME, providing structural support for cells and facilitating various signaling pathways that regulate tumor behavior. During HCC progression, the ECM undergoes extensive remodeling, which plays a pivotal role in the malignancy's development, invasion, and metastasis.

The ECM in HCC is characterized by an altered composition, including increased deposition of ECM proteins such as collagens, glycoproteins, and proteoglycans. This remodeling not only changes the physical properties of the ECM, leading to increased stiffness and altered mechanical signals, but also impacts the biochemical environment, thereby influencing the behavior of HCC cells. For instance, HCC cells grown in a matrix that mimics a cirrhotic liver exhibit increased proliferation and protein content compared to those grown in a less fibrotic environment, indicating that ECM composition and stiffness directly affect tumor cell behavior [47].

Moreover, the disorganized ECM can sensitize cancer cells to mechanical stress and alter signaling pathways, which may contribute to therapeutic resistance. In HCC, the interplay between the ECM and tumor cells facilitates epithelial-mesenchymal transition (EMT), a process that enhances the metastatic potential of cancer cells [48]. The ECM also acts as a reservoir for various cytokines and growth factors, further modulating the tumor microenvironment and supporting tumor growth [49].

The mechanisms of ECM remodeling in HCC are multifaceted. The interaction between HCC cells and non-cellular components of the TME, such as hepatic stellate cells and immune cells, contributes to ECM alterations. For example, tumor-associated macrophages (TAMs) can influence ECM remodeling through the secretion of proteolytic enzymes and growth factors, which promote tumor invasion and metastasis [50]. Additionally, signaling molecules released from HCC cells can activate fibroblasts and other stromal cells to modify the ECM composition, creating a feedback loop that supports tumor progression [51].

In summary, the remodeling of the extracellular matrix within the tumor microenvironment of HCC is a crucial mechanism that facilitates tumor growth and metastasis. This remodeling is driven by a complex interplay between tumor cells, stromal cells, and immune components, which together create a supportive environment for cancer progression. Understanding these mechanisms is essential for developing targeted therapies aimed at disrupting the supportive roles of the ECM in HCC [52][53][54].

5 Therapeutic Implications ​

5.1 Current Treatment Strategies ​

Hepatocellular carcinoma (HCC) is characterized by a complex interplay of molecular mechanisms that contribute to its initiation and progression. Understanding these mechanisms is crucial for developing effective therapeutic strategies.

The etiology of HCC is multifactorial, with key contributors including chronic viral infections (such as hepatitis B and C), alcohol abuse, metabolic dysfunction, and genetic predisposition. These factors often lead to a hypercarcinogenic state characterized by chronic inflammation, oxidative stress, and genomic alterations, ultimately resulting in hepatocarcinogenesis [55].

Molecularly, HCC progression is driven by a variety of genetic and epigenetic alterations. These include mutations in oncogenes and tumor suppressor genes, such as TP53 and β-catenin, which play critical roles in cell proliferation and apoptosis [56]. Furthermore, aberrations in signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, and WNT/β-catenin pathway, are implicated in the malignant transformation of hepatocytes [57].

The tumor microenvironment also significantly influences HCC development, with interactions between tumor cells and surrounding stromal cells facilitating tumor growth and metastasis [5]. Mechanisms such as epithelial-mesenchymal transition (EMT), which enhances the invasive potential of cancer cells, and the presence of cancer stem cells, which contribute to tumor recurrence and chemoresistance, are critical in this context [57].

Current treatment strategies for HCC are limited and often depend on the stage of the disease. Surgical resection and liver transplantation are considered curative for early-stage HCC; however, many patients present with advanced disease, making these options unfeasible [4]. For unresectable HCC, systemic therapies are the mainstay, with sorafenib being the most commonly used drug, although its efficacy is modest [5]. The emergence of new systemic therapies, including multi-target tyrosine kinase inhibitors and immunotherapies, has improved outcomes for some patients [58].

Despite these advancements, treatment resistance remains a significant challenge, often due to the heterogeneous nature of HCC and the presence of various molecular alterations [59]. Consequently, there is a pressing need for personalized treatment approaches that consider the unique molecular profile of each tumor [60].

In summary, the mechanisms underlying HCC are diverse and multifaceted, involving genetic mutations, altered signaling pathways, and interactions within the tumor microenvironment. The current treatment landscape is evolving, with a focus on targeted therapies and immunotherapy, aiming to improve patient outcomes and address the challenges of treatment resistance and tumor heterogeneity.

5.2 Emerging Therapies and Targeted Treatments ​

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy, characterized by complex biological mechanisms that drive its initiation and progression. The pathogenesis of HCC involves multiple factors, including genetic, epigenetic, and signaling pathway alterations, which contribute to tumorigenesis and therapeutic resistance.

The mechanisms underlying HCC can be broadly categorized into genetic alterations, epigenetic modifications, and dysregulated signaling pathways. Genetic alterations include recurrent mutations in oncogenes and tumor suppressor genes, which are critical for understanding the molecular basis of HCC. Recent advancements in next-generation sequencing technologies have identified numerous somatic mutations and single-nucleotide polymorphisms associated with HCC development (Niu et al., 2016)[4]. Furthermore, genomic instability and the aberrant activation of key signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and WNT/β-catenin pathway, have been implicated in the progression of HCC (Mir et al., 2021)[61].

Epigenetic alterations also play a significant role in HCC development. Changes in DNA methylation and histone modifications can lead to the silencing of tumor suppressor genes and the activation of oncogenes, contributing to the carcinogenic process. These epigenetic changes can be influenced by environmental factors such as chronic inflammation and oxidative stress, which are prevalent in liver disease (Fernández-Barrena et al., 2020)[9].

The therapeutic implications of understanding these mechanisms are profound. Targeting the identified molecular pathways has emerged as a promising strategy for HCC treatment. For instance, the multi-kinase inhibitor sorafenib has been established as a standard treatment for advanced HCC, although its efficacy is limited due to the heterogeneous nature of the disease and the presence of therapeutic resistance (Chen et al., 2019)[62]. Novel therapies are being developed to overcome these challenges, including combinations of targeted therapies and immunotherapies, which aim to enhance the antitumor effects and address the tumor microenvironment's influence on treatment response (Wang et al., 2023)[34].

Emerging therapies focus on exploiting specific molecular targets identified through comprehensive genomic and epigenomic analyses. For example, the development of agents targeting the insulin-like growth factor (IGF) pathway and other critical signaling cascades is being explored as a means to improve therapeutic outcomes (Marks & Yee, 2016)[63]. Additionally, the identification of biomarkers associated with HCC can guide the selection of personalized treatment approaches, allowing for more effective management of this challenging malignancy (Wang & Deng, 2023)[34].

In conclusion, the intricate mechanisms of HCC involve a combination of genetic and epigenetic alterations alongside disrupted signaling pathways. A deeper understanding of these mechanisms is essential for developing novel targeted therapies and improving patient outcomes in HCC. Continued research into the molecular characteristics of HCC will facilitate the advancement of precision medicine approaches tailored to individual patient profiles.

5.3 Future Directions in HCC Research ​

Hepatocellular carcinoma (HCC) is characterized by a multifaceted molecular pathogenesis involving various genetic, epigenetic, and environmental factors. The mechanisms underlying HCC development and progression are complex, and understanding these mechanisms is crucial for the development of effective therapeutic strategies.

The pathogenesis of HCC is significantly influenced by chronic liver conditions such as viral hepatitis, excessive alcohol consumption, and cirrhosis, which contribute to the carcinogenic process. The development of HCC is associated with two primary pathogenic mechanisms: (1) cirrhosis linked to hepatic regeneration following tissue damage from hepatitis infections, toxins (e.g., alcohol, aflatoxin), or metabolic influences, and (2) mutations in oncogenes or tumor suppressor genes, which disrupt critical cellular signaling pathways (Whittaker et al., 2010)[10].

Recent advancements in next-generation sequencing have unveiled numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways. These alterations contribute to genomic instability, single-nucleotide polymorphisms, and somatic mutations that are implicated in HCC initiation and progression (Niu et al., 2016)[4]. Furthermore, molecular signaling pathways such as the mitogen-activated protein kinase pathway, phosphoinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, and WNT/β-catenin pathway play significant roles in HCC pathogenesis by regulating cellular proliferation, differentiation, and survival (Mir et al., 2021)[61].

Therapeutically, the management of HCC has evolved with a focus on targeted therapies that exploit these molecular mechanisms. Traditional treatment options such as surgical resection and liver transplantation are limited by the advanced stage at which HCC is often diagnosed. Current systemic therapies include sorafenib, which, despite its modest overall survival benefit, represents a significant advancement in the treatment of unresectable HCC (Nguyen et al., 2015)[55]. However, there is a critical need for the development of more effective therapies that target specific molecular pathways involved in HCC progression.

Emerging therapeutic strategies, including immune-targeted therapies and traditional Chinese medicine monomers, are being explored to enhance treatment efficacy. The role of long non-coding RNAs (lncRNAs) in regulating gene expression and their potential as biomarkers and therapeutic targets are also gaining attention (Sheng et al., 2022)[64]. Additionally, the identification of novel biomarkers associated with HCC metastasis, such as circulating tumor cells and circulating tumor DNA, could significantly improve early detection and therapeutic monitoring (Wei et al., 2025)[65].

Future directions in HCC research should focus on elucidating the intricate molecular mechanisms underlying HCC progression, including the interplay between genetic and epigenetic factors. Integrative multi-omics approaches can facilitate the identification of molecular subtypes of HCC, which may lead to more personalized therapeutic strategies (Wu et al., 2020)[60]. Furthermore, ongoing studies should aim to enhance our understanding of the tumor microenvironment and its impact on HCC biology, which could unveil new therapeutic targets and strategies.

In conclusion, the mechanisms of HCC are complex and multifactorial, involving genetic mutations, epigenetic alterations, and dysregulated signaling pathways. Continued research into these mechanisms is essential for the development of innovative therapeutic strategies and the identification of potential biomarkers, ultimately improving patient outcomes in HCC.

6 Conclusion ​

The mechanisms underlying hepatocellular carcinoma (HCC) are complex and multifaceted, involving a combination of genetic predispositions, environmental factors, and intricate interactions within the tumor microenvironment. The primary findings of this review indicate that chronic viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease are significant risk factors contributing to HCC development. Genetic alterations, particularly mutations in oncogenes and tumor suppressor genes, along with epigenetic changes, play critical roles in the pathogenesis of HCC. Furthermore, the tumor microenvironment, including the roles of hepatic stellate cells, immune cells, and extracellular matrix remodeling, significantly influences tumor progression and therapeutic responses. Current treatment strategies for HCC remain limited, particularly for advanced stages of the disease, underscoring the urgent need for novel therapeutic approaches that target specific molecular pathways. Future research should focus on the development of personalized treatment strategies based on the molecular characteristics of HCC, as well as the exploration of emerging therapies, including immunotherapy and targeted treatments. Continued investigation into the complex interplay of genetic, epigenetic, and environmental factors will be essential for improving patient outcomes and developing effective interventions against HCC.

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