A review on liver cancer: Challenges, molecular insights and future directions in management

 Corresponding author: Sundara Vijayan S Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. A review on liver cancer: Challenges, molecular insights and future directions in management Sundara vijayan S , Subramanian L, Muniyandi M, Ruthra P, Vijaya lakshmi P and Rajesh M Department of Pharmaceutics, Sankaralingam bhuvaneswari college of pharmacy, Sivakasi, Tamilnadu, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 Publication history: Received on 05 October 2025; revised on 18 November 2025; accepted on 20 November 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.2.1023 Abstract Liver cancer, predominantly hepatocellular carcinoma (HCC), poses a major global health challenge due to late diagnosis, poor prognosis and limited therapeutic success. Despite advances in molecular and immunological research, the complex pathogenesis and tumor microenvironment hinder effective management. This review summarizes current insights into etiology, molecular mechanisms, diagnostic limitations and therapeutic strategies, emphasizing genetic, epigenetic, viral, metabolic and environmental factors driving hepatocarcinogenesis. Recent multi-omics and liquid biopsy technologies enable early detection, biomarker discovery and personalized therapy. Precision oncology, incorporating immunotherapy, targeted agents and combination regimens, has improved outcomes, though resistance and recurrence remain challenges. Liver transplantation offers curative potential but faces donor scarcity and posttransplant complications. Emerging innovations such as molecular profiling, neoadjuvant immunotherapy and advanced drug delivery systems promise enhanced efficacy. Integrating spatial multi-omics, single-cell transcriptomics and Artificial Intelligence will refine diagnosis, prognosis and therapy, transforming liver cancer into a more manageable disease. Keywords: Liver Cancer; Hepatocellular Carcinoma; Molecular Mechanisms; Multi-Omics; Immunotherapy; Targeted Therapy; Biomarkers; Precision Oncology 1. Introduction Liver cancer remains a major global health challenge due to its high incidence, late diagnosis and limited effective treatment options. The most prevalent primary liver cancer, hepatocellular carcinoma (HCC), makes up 75–85% of cases and is frequently discovered when curative treatments are no longer effective. Even with advancements in our knowledge of the pathophysiology of liver cancer, including molecular changes and the tumour microenvironment, early identification is still not ideal and existing treatment approaches usually face resistance and recurrence1. Advances in molecular biology and immunotherapy have revealed intricate interactions within the liver tumour microenvironment, which impact tumour growth and treatment response2. For example, targeting tumor-associated macrophages and immune cells offers interesting therapeutic pathways, but tumour heterogeneity and the immunosuppressive milieu represent considerable challenges3. New biomarkers and multiomics techniques have the potential to enhance early diagnosis and allow for individualised treatment regimens based on each tumor's genetic makeup, according to recent study4. Furthermore, novel approaches to drug administration and combination therapy that combine traditional and targeted treatments hold potential for increasing therapeutic efficacy while reducing toxicity5. Ongoing efforts concentrate on honing molecular insights and converting these discoveries into useful therapeutic applications in light of these difficulties and developments. In order to promote better results for patients everywhere, this review attempts to thoroughly examine the molecular processes, present difficulties and potential future prospects in the treatment of liver cancer. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 540 2. Etiology and risk factors Complex interactions between several etiological variables that promote chronic liver damage, inflammation and genetic changes lead to the development of liver cancer, mainly HCC. Chronic liver damage brought on by toxins, viral infections, or metabolic dysfunction is the first step in molecular pathogenesis. This leads to cirrhosis, fibrosis, chronic inflammation and eventually carcinogenesis. Immune modulation, chromosomal instability, cell cycle dysregulation, epithelial to mesenchymal transition, DNA methylation alterations and dysregulated microRNAs (miRNAs) are important processes6. Persistent inflammation and genetic damage caused by chronic hepatitis B and C virus infections continue to be major risk factors globally, encouraging the malignant transformation of hepatocytes. The viral components maintain liver fibrosis and accelerate the development of HCC6 by activating pattern recognition receptors and downstream inflammatory pathways. By promoting oxidative stress, DNA damage and immunological dysregulation all of which encourage hepatocyte death and compensatory regeneration cycles that favour malignant clones alcoholic liver disease increases risk7. Figure 1 Liver Cancer Risk Factors and Regional Prominence A significant contributing factor to HCC is metabolic dysfunction-associated steatotic liver disease (MASLD), which is becoming more common as obesity and diabetes epidemics spread. Regardless of viral infection, lipid buildup accelerates carcinogenesis by inducing inflammatory signalling and epigenetic changes. By resulting in DNA adducts and p53 mutations, environmental exposures like aflatoxins work in concert with viral hepatitis to intensify mutagenic processes8. According to recent multi-omics investigations, genetic alterations in pathways such as Wnt/β-catenin, Notch, PI3KAKT-mTOR and insulin-like growth factor are responsible for HCC spread, apoptosis evasion and proliferation9. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 541 Additionally, although being less frequent, paediatric HCC is linked to unique molecular pathways and genetic predispositions, highlighting the diversity of liver cancer aetiologies10. All things considered, the etiology of liver cancer is a combination of metabolic, genetic, environmental and viral variables that lead to a variety of molecular changes. Developing focused preventative and treatment plans requires an understanding of these unique and overlapping pathways11. Figure 2 Risk-Guided Liver Cancer Screening and Management Pathway 3. Pathogenesis and molecular mechanisms Chronic liver damage causes molecular and cellular changes that drive the complicated pathophysiology of liver cancer, primarily HCC. Fibrosis and cirrhosis are caused by persistent inflammation, which is frequently brought on by hepatitis virus infections or metabolic inefficiency. This creates a milieu that is favourable for malignant transformation12. Immune evasion strategies, chromosomal instability, epigenetic changes and dysregulation of cell cycle control are important biological processes. Major signalling pathways, including as PI3K/Akt/mTOR and Ras/Raf/MEK/ERK are triggered by the activation of receptor tyrosine kinases such hepatocyte growth factor receptor (MET), which promotes angiogenesis, tumour cell survival and proliferation13. Through the HBV X protein (HBx), which interferes with cell cycle checkpoints and amplifies oncogenic signalling pathways, the chronic hepatitis B virus (HBV) directly causes cancer and aids in the development and spread of tumours14. The development of HCC is strongly influenced by elements of the tumour microenvironment, particularly polarised macrophages and immune cells. Through the release of proangiogenic and immunosuppressive molecules, M2polarized tumor associated macrophages (TAMs) promote tumour development and help in immune evasion and metastasis, making effective therapy more difficult15. These results highlight the dynamic interaction between immune milieu and tumour cells in the pathobiology of liver cancer. he molecular heterogeneity in HCC has been further revealed by genomic and immunological profiling investigations, which have identified important driver mutations and deregulated pathways including Wnt/β-catenin signalling, which is typically dysregulated in HCC and plays a crucial role in liver metabolism and cell destiny16. These discoveries open the door for precision medicine strategies that focus on certain molecular changes. In conclusion, a complex interaction of genetic, epigenetic, environmental and immunological variables drives the pathogenesis of liver cancer. The development of innovative treatment and diagnostic approaches to enhance patient outcomes is made possible by advances in our knowledge of these systems. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 542 Figure 3 The main mechanism of viral infection-induced hepatocellular carcinoma 4. Diagnostic and prognostic approaches The use of multi-omics technology, enhanced imaging and the identification of biomarkers have all led to substantial advancements in the diagnostic and prognostic methods for liver cancer, especially HCC. Since approximately 20–30% of patients are eligible for curative therapy at diagnosis, early and accurate identification is still difficult but essential to improving survival rates17. Creative tactics Combining proteomic, metabolomic, transcriptomic and genomic data has World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 543 revealed a large number of putative biomarkers. These include circulating microRNAs, extracellular vesicle (EV) derived compounds and tumor-specific gene alterations. These offer better sensitivity and specificity than traditional markers18. An epigenetic biomarker called methylated SEPT9 (mSEPT9) DNA has the potential to identify primary liver cancer with a high degree of diagnostic precision. Its inclusion enhances sensitivity, particularly for advanced illness stages, in conjunction with methylation patterns in RASSF1A and other genes. In order to increase the clinical value of mSEPT9 tests, ongoing efforts are being made to optimise them for early-stage detection utilising next-generation sequencing methods19. Ultrasonography and other imaging modalities are still essential for regular monitoring. However, because to operator dependence and tumor location, ultrasonography alone is not sensitive enough detecting tiny or early-stage tumours. In contrast to imaging or isolated biomarkers, recent clinical studies have shown that combining ultrasonography with serum biomarkers such as alpha-fetoprotein (AFP), serum amyloid A (SAA), and C-reactive protein (CRP) greatly improves diagnostic performance, achieving better sensitivity and specificity20. The identification of circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and tumor-derived EVs is made possible by liquid biopsies, which are minimally invasive procedures. These techniques make prognostication and dynamic disease monitoring easier. For example, the existence and aggressiveness of tumours are correlated with increased levels of certain miRNAs, such as miR-21 and miR-144 inside EVs. Despite the potential of liquid biopsy technologies, authoritative guidelines now advise using them only in research settings till more validation is obtained. Certain tumor-associated protein patterns and proteoforms with possible diagnostic and prognostic uses are revealed by proteomic analysis. These biomarkers might supplement genetic knowledge by forecasting treatment outcomes and disease progression. When combined, multi-dimensional biomarkers, sophisticated imaging and molecular diagnostics offer a strong foundation for enhancing liver cancer early detection and prognostic classification, which is essential for customising treatment plans and enhancing patient outcomes21. 5. Current therapeutic strategies The interdisciplinary strategy used in current liver cancer treatment plans is based on the patient's health, liver function and tumour stage. The European Association for the Study of the Liver (EASL) 2024 recommendations state that the focus of early-stage care of HCC is on curative therapies, including liver transplantation, surgery and ablation procedures. Recent developments include improved liver transplantation criteria and minimally invasive surgical techniques, which are backed by surveillance systems that use cutting-edge imaging for better patient selection and early identification22. Once a restricted choice, radiation therapy is now an essential one, particularly when used in conjunction with systemic medications. In 2022, the Japanese Society of Hepatology emphasised liver transplantation (LT) as the best option for qualified applicants, especially those who met the Milan or extended criteria. Long-term survival is increased by bridging and downstaging treatments, which make some patients who were previously unsuitable for LT candidates. However, there are geographical differences in the availability and distribution of organs, which calls for specialised management techniques23. These guidelines are echoed in the 2022 recommendations from the American Association for the Study of Liver Diseases (AASLD), which emphasises tailored therapy depending on liver function and tumour load. For localised lesions with sufficient hepatic reserve, surgical excision is still the preferable treatment. For tumours that cannot be removed, locoregional treatments such as transarterial chemoembolization (TACE) and radiofrequency ablation offer substitutes or supplements. Notably, new systemic treatments that combine antiangiogenic drugs and immune checkpoint inhibitors have changed the landscape of treatment and increased survival in advanced illness24. The 2025 update from the U.S. National Cancer Institute offers a thorough overview of treatment categorised by liver function and illness stage. Resection, transplantation and several tumour ablation methods are alternatives for localised illness. Treatments include TACE, radiotherapy and new systemic medicines like tyrosine kinase inhibitors and immunotherapies are beneficial for both locally progressed and metastatic HCC. Coordination of multidisciplinary treatment is necessary to maximise results25. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 544 Last but not least, the historic Regorafenib after Sorafenib in patients with hepatocellular carcinoma (RESORCE) study by Bruix in 2022 shows that regorafenib is an effective second-line treatment after sorafenib, which represents a major advancement in molecularly targeted treatment for advanced HCC. This has increased the range of available treatments and opened the door for personalised medicine strategies that combine clinical care with biological insights26. In conclusion, improvements in systemic medicines, locoregional interventions, transplantation and surgery are all included into the current therapeutic approaches for liver cancer. A patient-centric approach is ensured by ongoing guidelines revision that takes into account new data, enhancing survival and quality of life in this complicated cancer. 6. Challenges in liver cancer management Despite advancements in treatment, gains in patient outcomes are limited by the major management issues associated with liver cancer, particularly HCC. The often-late diagnosis of liver cancer is a major problem. The majority of patients are discovered at intermediate or advanced stages, when there are no longer any feasible curative alternatives, such as liver transplantation or surgical resection, significantly decreasing the likelihood of life27. This issue is made worse by the present monitoring systems low sensitivity and their restricted use in high-risk groups. There is still a need for improved early detection techniques that make use of biomarkers and imaging developments. The effectiveness of therapy is further complicated by tumour heterogeneity. Variability in treatment responses and the emergence of resistance to systemic therapy, such as targeted medicines and immunotherapies, are caused by molecular and genetic diversity both within and across tumours28. The one-size-fits-all therapy paradigm is challenged by this cellular heterogeneity, which calls for individualised strategies based on molecularprofiling. For certain patients, LT may be curative, however there are several challenges. Its wider use is complicated by strict eligibility requirements, acute organ shortages and post-transplant tumour recurrence concerns. Furthermore, there is a difficult therapeutic balance since the immunosuppressive treatment needed following LT may paradoxically encourage tumour growth or subsequent cancers29. Although they have not yet been standardised, bridging medicines to downstage tumours and increase transplant candidacy show promise. Technological developments that might improve diagnosis and therapy classification include pathomics and Artificial Intelligence-based histopathology image analysis. But there are still issues with standardising methods, confirming results in bigger groups and incorporating these tools into therapeutic procedures30. Widespread adoption is further slowed by computational requirements and the requirement for extensive annotated datasets. Lastly, there are particular difficulties due to the evolving epidemiology of liver cancer, which is increasingly influenced by metabolic dysfunction-associated fatty liver disease (MASLD), obesity and diabetes. Frameworks for prevention and therapy that were primarily created for virus-associated HCC are complicated by these non-viral risk factors, necessitating specialised public health initiatives and therapeutic methods31. In conclusion, the best care of liver cancer is hampered by a number of important issues, including late-stage detection, tumour heterogeneity, restricted access to transplants, impediments to technology integration and changing epidemiology. Coordinated efforts involving enhanced surveillance, molecular characterisation, novel treatments and individualised treatment algorithms based on cutting-edge research and interdisciplinary cooperation are needed to address them. 7. Molecular targets and novel therapeutics Hepatocellular carcinoma, the most common kind of liver cancer, has a complex molecular landscape with a wide range of potential treatment options. Utilising these molecular abnormalities to create immunotherapeutic and targeted approaches to enhance patient outcomes has been the focus of recent developments. Mabeta and Steenkamp (2024) provide a thorough analysis of the uses of immunotherapy and molecularly targeted drugs, highlighting the use of both strategies to combat the resistance mechanisms present in solid tumours32. The complex tumour biology of HCC is reflected in the key pathways addressed, which include VEGF signalling, the Ras/Raf/MEK/ERK cascade and immunological checkpoints. Suzuki draw attention to the immunological and molecular environment that supports the pathophysiology of HCC and the response to treatment. They highlight targets like glypican-3 (GPC3), which, in spite of difficulties with heterogeneous tumour expression, is becoming more and more acknowledged as a potential antigen World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 545 for chimeric antigen receptor (CAR)-T cell treatments. Other exciting research directions include developments in CARNK and TCR-T treatments, which seek to improve anti-tumor effectiveness while reducing off-target consequences33. In their discussion of the development of molecular-targeted medicines, Yan point out that multikinase inhibitors such as lenvatinib and sorafenib continue to be first-line therapy. By blocking important kinases like VEGFR and PDGFR, these substances have anti-proliferative and anti-angiogenic actions. In order to guide patient selection for targeted medicines and provide prediction value for therapy response, novel biomarkers like FGF19 have developed34. The study emphasises that in order to successfully use precision medicine, these indicators must be externally validated. Recent developments in systemic treatment, such as the approval of immune checkpoint inhibitors and combination regimens that utilise both immunomodulatory and anti-angiogenic properties, are reviewed by Arao. By addressing both the immunosuppressive tumour microenvironment and tumour cells, these therapeutic developments mark a paradigm change and enhance survival rates. However, treatment predictability is complicated by the geographical heterogeneity of immune markers like PD-L1, which calls for improved biomarker frameworks35. According to Deng new small-molecule medications that target receptors with high specificity in particular, fibroblast growth factor receptor 4 (FGFR4) offer therapeutic leverage because to its distinct structural characteristics in liver cells. In early-phase studies, a number of selective FGFR4 inhibitors showed encouraging effectiveness and safety, which represents a major advancement in targeted HCC treatment. In contrast to the more general kinase inhibition of previous medications, this precise targeting may lessen off-target effects and enhance therapeutic results36. 8. Experimental models and translational research Strong experimental models are essential to liver cancer research in order to understand tumour biology, clarify underlying molecular pathways and aid in the creation of efficient treatments. Advanced models that more closely resemble in vivo circumstances are required since traditional two-dimensional cell cultures are unable to replicate complex tumour heterogeneity and microenvironment interactions. Three-dimensional (3D) culture techniques, such organoids and spheroids, have recently gained attention because they more accurately replicate the architecture, cellular variety and microenvironmental dynamics of liver tumours than monolayer cultures. Pastore highlight their potential for tailoring cancer therapy by highlighting their use in drug response assessment and resistance mechanism research. Continuous improvements improve their prognostic accuracy and translational significance in spite of obstacles including culture standardisation and inadequate microenvironment representation37. Carvalho draw attention to the novel liver-on-a-chip (LoC) technology, which replicates liver physiology and tumour microenvironments, especially in hypoxic circumstances that are common in tumours, by combining microfluidic devices with computer models. By combining experimental and in silico methods, the limits of traditional models are overcome and accurate drug screening and a deeper comprehension of tumour growth pathways are made possible38. Animal models are still essential and patient-derived xenografts (PDXs) and genetically modified mouse models (GEMMs) are crucial. In their thorough review of HCC experimental systems, Kim points out that PDXs maintain patient tumour heterogeneity, which is essential for preclinical testing, whereas GEMMs enable molecular dissection of hepatocarcinogenesis. However, in order to improve translational accuracy, obstacles including interspecies variations, ethical issues and high costs call for supplementary models and improved methods39. The immunological milieu around liver tumours has been better understood because to developments in single-cell sequencing combined with mouse models. Tumor-associated neutrophils are identified as possible targets for immunotherapy by Liao, who also explain the classification of tumour immune microenvironment (TIME) subgroups with different clinical outcomes. This emphasises how crucial it is to combine multi-omics and experimental models in order to identify therapeutic targets and characterise the immune landscape40. In their thorough assessment of in vitro liver cancer models, Shao clarify the functions of organoids, co-cultures and monocultures in drug development, biomarker identification and mechanistic investigation. To speed up translational research from the bench to the bedside and eventually pursue precision medicine in the treatment of liver cancer, advancements in these models are crucial41. In conclusion, the use of sophisticated animal models, organ-on-chip technologies, advanced 3D cultures and integrated omics techniques all work together to promote translational liver cancer research. By advancing our knowledge of hepatocarcinogenesis and therapeutic response, these complex experimental systems encourage the development of tailored treatments and open the door to better clinical results. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 546 Figure 4 Schematic diagram Construction and application of liver cancer models in vitro Figure 5 A, Advances in Spheroids B, Organoids for Liver Cancer Research Future directions Although survival rates have increased due to developments in targeted treatments and a better knowledge of liver cancer biology, there are still major obstacles to overcome in order to avoid recurrence and overcome drug resistance. Precision medicine, early diagnosis and customised multimodal therapy combining systemic, locoregional and immunotherapeutic methods will become more and more important components of future management regimens42. Combination therapies have become more popular in recent years, replacing traditional monotherapy techniques. Advanced HCC has been shown to respond better to combination regimens that incorporate immune checkpoint World Journal of Biology Pharmacy and Health Sciences, 2025, 24(02), 539-550 547 inhibitors, antiangiogenic medicines and TKIs (tyrosine kinase inhibitors). These combinations constitute a paradigm change in second-line treatment as they seek to improve immune microenvironment regulation while reducing recurrence rates43. In order to improve patient outcomes and reduce systemic toxicity, efforts are also being made to optimise the timing and sequencing of these medicines. Early detection is a major priority in the management of liver cancer. It is anticipated that the addition of liquid biopsy platforms and new imaging biomarkers would revolutionise screening accuracy. Technologies for circulating tumour DNA and RNA enable the detection of minimal residual illness and real-time therapy response monitoring. The molecular heterogeneity of HCC has also been better understood because to next-generation sequencing (NGS), which allows the implementation of tailored and targeted treatments that correspond to certain mutational patterns. The management of recurring or incurable liver tumours still heavily relies on liver transplantation. But there are still issues with donor scarcity, post-transplant recurrence and accurate candidate selection. In order to increase survival rates and reduce the risk of rejection, future transplantation procedures are investigating integration with neoadjuvant immunotherapy and genetic profiling44. Research on regenerative scaffolds and organ bioengineering in parallel offers promise for overcoming donor restrictions and lowering the likelihood of recurrence in transplant patients. A future of precision-guided therapies is also hinted at by emerging therapeutic technology. By combining single-cell transcriptomics with spatial multiomics, tumour subtypes and immunological landscapes that influence treatment choices are being revealed45. Moreover, the use of Artificial Intelligence (AI) is expected to enhance predictive modeling for patient prognosis, optimize imaging evaluation and customize dose schedules based on real-time feedback. Finally, translational frameworks integrating molecular, radiological and immunological data herald an era of completely personalized cancer care. The implementation of multi-omics-guided algorithms in clinical settings and the continued adoption of liquid biopsy testing will play decisive roles in reducing mortality from hepatocellular carcinoma46. The future of liver cancer treatment is defined by these developments taken together, which highlight an integrated approach from early molecular diagnoses to biomarker-based, customised therapy and transplantation enhancement. 9. Conclusion Liver cancer continues to represent one of the most formidable global health challenges due to its complex pathogenesis, molecular heterogeneity and limited curative treatment options. Despite remarkable advances in understanding its molecular biology and tumor microenvironment, translating these insights into effective clinical interventions remains a major obstacle. Emerging evidence highlights that individualized, multimodal management integrating surgical, locoregional and systemic therapies offers the greatest promise for improving survival and quality of life. The evolution of molecular diagnostics, precision oncology and immune checkpoint modulation has transformed the therapeutic landscape, shifting focus from traditional chemotherapy toward targeted and immunotherapeutic paradigms capable of overcoming resistance and recurrence. The growing integration of multi-omics technologies, including genomics, transcriptomics, proteomics and metabolomics, provides an unprecedented ability to identify predictive biomarkers and therapeutic targets. These advances enable the adaptation of personalized treatment algorithms grounded in tumor biology and patient-specific molecular profiles. Similarly, innovations such as liquid biopsies and circulating tumor DNA analysis bridge diagnostic and monitoring gaps, facilitating real-time disease assessment and earlier relapse detection. In tandem, bioinformatics, Artificial Intelligence and machine learning approaches are redefining liver cancer classification, enabling continuous refinement of risk stratification and prognosis models that can guide clinical decision-making more accurately. Parallel strides in regenerative medicine and transplantation research are addressing long-standing challenges, including donor shortages and post-transplant recurrence. Integrating neoadjuvant immunotherapy and molecular profiling into transplant protocols holds substantial potential to improve graft outcomes and reduce recurrence risk, marking a new era in transplant oncology. Advances in organ bioengineering and bioprinting could further extend these capabilities in the coming decade. The path forward for liver cancer management lies in uniting technological innovation with biological insight to design comprehensive, patient-centered frameworks. Future research must emphasize translational applications bridging laboratory discoveries with clinical practice to ensure that innovations in molecular and immunological research translate into tangible population-level outcomes. Ultimately, sustained cross-disciplinary collaboration, robust clinical validation and equitable access to new technologies will be pivotal in transforming liver cancer from a fatal malignancy into a clinically manageable disease.