Halting and Slowing Fibrosis Progression in Liver Cancer:

Current Approaches and Future Directions

Ian Y.H. Chua

1, 2, 3, 4

18 February 2025

Abstract

Liver cancer, particularly hepatocellular carcinoma (HCC), often arises in the context of

chronic liver disease and underlying brosis or cirrhosis. Fibrosis progression is a critical

factor in the development and worsening of HCC, with cirrhosis present in up to 90% of

cases. Addressing liver brosis is essential not only for preventing cancer onset but also

for improving therapeutic outcomes and overall survival in patients with liver cancer. This

paper discusses the relationship between brosis progression and liver cancer

development, explores current treatment options aimed at halting brosis, and examines

emerging therapies targeting the brotic microenvironment to improve liver cancer

management.

Introduction

Fibrosis, characterized by excessive deposition of extracellular matrix (ECM)

components, results from chronic liver injury due to various etiologies, including viral

hepatitis, alcohol-related liver disease, and nonalcoholic steatohepatitis (NASH).

Persistent brosis can progress to cirrhosis, which creates a pro-tumorigenic

environment conducive to hepatocellular carcinoma (HCC) development. The interplay

between chronic inammation, brosis, and oncogenesis highlights the importance of

early intervention to prevent brosis progression in at-risk patients. Even after the onset

of liver cancer, managing brosis can improve liver function, reduce complications, and

enhance the eicacy of cancer-directed therapies. Therefore, halting or slowing brosis

progression represents a critical component of comprehensive liver cancer care.

Pathophysiology of Fibrosis and Its Role in Liver Cancer Development

Fibrosis progression is driven by chronic liver injury, which activates hepatic stellate cells

(HSCs). Activated HSCs produce brogenic cytokines, such as transforming growth

factor-beta (TGF-β), and secrete ECM proteins that disrupt liver architecture. This brotic

environment fosters genetic mutations, promotes angiogenesis, and enhances cellular

proliferation—key processes in hepatocarcinogenesis. In advanced brosis and

cirrhosis, regenerative nodules surrounded by brous bands further increase the risk of

malignant transformation. Understanding this brotic-cancer link underscores the

necessity of targeting brosis to prevent HCC development and progression.

Current Treatment Strategies for Halting Fibrosis Progression in Liver Cancer

Addressing Underlying Causes of Liver Injury

• Viral Hepatitis: Eradication of hepatitis C virus (HCV) with direct-acting

antivirals and suppression of hepatitis B virus (HBV) with nucleos(t)ide analogs

can signicantly reduce brosis progression and lower HCC risk.

• Alcohol-Related Liver Disease: Sustained alcohol abstinence remains vital in

reducing brosis and preventing further liver damage.

• NAFLD/NASH: Lifestyle modications, including weight loss, diet, and exercise,

are primary interventions. Pharmacological treatments, such as obeticholic acid

and pioglitazone, are being explored to manage brosis in NASH patients.

Antibrotic Agents and Their Role in Liver Cancer Prevention

• Obeticholic Acid: An FXR agonist shown to reduce brosis in NASH and

potentially lower HCC risk.

• Lanibranor: A pan-PPAR agonist that improves brosis and may have indirect

benets in reducing HCC incidence.

• Pirfenidone and Selonsertib: Investigated for antibrotic eects, though their

impact on liver cancer prevention requires further study.

• Statins: Beyond lipid-lowering properties, statins exhibit antibrotic and

antitumor activities, reducing HCC risk in patients with chronic liver disease.

Emerging Therapeutic Approaches Targeting Fibrosis in Liver Cancer

Targeting the Tumor Microenvironment (TME)

The brotic stroma within the liver cancer microenvironment plays a critical role in

tumor progression and therapy resistance. Strategies include:

• TGF-β Inhibitors: Block brogenic signaling pathways to reduce ECM deposition

and tumor-promoting inammation.

• Integrin Inhibitors: Disrupt cell-ECM interactions, limiting tumor growth and

metastasis.

• Matrix Metalloproteinase (MMP) Modulators: Regulate ECM remodeling and

potentially reduce brotic barriers to drug delivery.

Gene and Cell-Based Therapies

• CRISPR/Cas9 Gene Editing: Targets brosis-related genes to halt progression

and improve liver function in cancer patients.

• Mesenchymal Stem Cell Therapy: Demonstrates potential in reducing brosis

and enhancing antitumor immunity.

• Exosome-Based Delivery: Provides targeted delivery of antibrotic and

anticancer agents, minimizing o-target eects.

Integrating Antibrotic Therapy with Liver Cancer Treatment

Combining antibrotic therapies with standard liver cancer treatments, such as

transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and systemic

therapies (e.g., sorafenib, lenvatinib, and immunotherapies), may improve treatment

eicacy. Reducing brosis enhances drug penetration and mitigates liver function

deterioration during cancer therapy. Personalized treatment plans considering brosis

stage, tumor burden, and liver reserve are essential for optimizing outcomes.

Conclusion

Fibrosis progression plays a pivotal role in liver cancer development and prognosis.

Targeting brosis not only aids in preventing HCC but also improves therapeutic

outcomes in patients with established liver cancer. While current treatments primarily

focus on underlying liver injury, emerging antibrotic therapies oer promising avenues

to slow brosis progression and enhance cancer care. Continued research and clinical

trials are imperative to rene these strategies and integrate them into standard liver

cancer management protocols.

Acknowledgments

This paper was developed with the assistance of ChatGPT 4.0, which provided insights and renements in the

articulation of philosophical and scientic concepts.

Founder/CEO, ACE-Learning Systems Pte Ltd.

M.Eng. Candidate, Texas Tech University, Lubbock, TX.

M.S. (Anatomical Sciences Education) Candidate, University of Florida College of Medicine, Gainesville, FL.

M.S. (Medical Physiology) Candidate, Case Western Reserve University School of Medicine, Cleveland, OH.

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