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Current and emerging strategies for the prevention of hepatocellular carcinoma

Abstract

Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.

Key points

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide; scalable, population-wide preventive strategies targeting risk factors (such as viral hepatitis infection, alcohol use and metabolic syndrome) are urgently needed.

HCC-preventive approaches target modifiable risk factors, with lifestyle changes, antiviral agents and pharmacological interventions showing efficacy in reducing the progression of underlying chronic liver diseases.

Antiviral therapies for hepatitis B virus, coupled with vaccination, have notably decreased HCC incidence by mitigating new viral transmission and liver disease progression, but complete viral eradication remains a challenge.

Research indicates that hypoglycaemic agents, lipid-lowering drugs and aspirin potentially reduce HCC risk, but further prospective investigation with randomized controlled trials is required.

Emerging medications and bioactive natural products have shown potential in disrupting tumorigenic pathways and reducing HCC risk, mostly in mouse models, but more evidence is needed in human studies.

A multifaceted approach that combines pharmacological, lifestyle and dietary strategies shows promise for tailored HCC prevention, but rigorous randomized trials are needed to validate clinical efficacy and safety.

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Fig. 1: Mechanisms of hepatocellular carcinoma prevention by hypoglycaemic agents.

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Acknowledgements

J.D.Y. is funded by the National Institutes of Health (NIH) (K08CA259534; R21CA280444). A.V. is funded by the NIH (1U01CA283931-01).

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Authors and Affiliations

Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Yee Hui Yeo & Ju Dong Yang

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

Manal Abdelmalek

Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL, USA

Seema Khan

Division of Gastroenterology, Duke University Health System, Durham, NC, USA

Cynthia A. Moylan

Gastrointestinal & Other Cancers Research Group, NCI, Rockville, MD, USA

Luz Rodriquez

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Augusto Villanueva

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Ju Dong Yang

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Ju Dong Yang

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Yee Hui Yeo

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J.D.Y. and Y.H.Y. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Ju Dong Yang.

Ethics declarations

Competing interests

J.D.Y. provides a consulting service for AstraZeneca, Eisai, Exact Sciences, Exelixis, Fujifilm Medical Sciences, Merck and Gilead Sciences. A.V. has received consulting fees from FirstWorld, Pioneering Medicine and Genentech; advisory board fees from BMS, Roche, AstraZeneca, Eisai and NGM Pharmaceuticals; research support from Eisai; and has stock options from Espervita. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Peter Galle, Hidenori Toyoda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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