Pharmacological chemoprevention of hepatocellular carcinoma: hype, hope, or reality?

Hepatocellular carcinoma (HCC) remains a major global health challenge and is increasingly linked not only to chronic viral hepatitis and alcohol exposure, but also to metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and dysglycemia. Advanced fibrosis and cirrhosis are the main precancerous conditions for hepatocarcinogenesis, making chemoprevention a rational strategy for individuals at risk of developing primary HCC or experiencing recurrence after treatment. However, fibrosis regression, steatohepatitis resolution, and steatosis reduction are biologically plausible but unvalidated surrogate endpoints for HCC chemoprevention. While antiviral therapy and hepatitis B vaccination have proven effective in preventing liver cancer, there is currently no established pharmacological approach for MASLD-related HCC. Among available agents, statins have shown the most consistent observational evidence of benefit, while data for aspirin and metformin are less robust or inconclusive. Newer compounds targeting key pathogenic pathways involved in steatosis, inflammation, and fibrogenesis are of significant interest. Semaglutide, lanifibranor, and resmetirom may indirectly reduce HCC risk by improving MASLD-related disease activity, although direct evidence for cancer prevention is still lacking. Other potential candidates, such as angiotensin-converting enzyme inhibitors, aripiprazole, and RNA-based strategies, are still in the investigational stages. Advances in this field will require improved risk assessment, validated biomarkers, and prospective trials to determine whether reducing fibrosis can lead to meaningful reductions in HCC incidence.