Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are the most common chronic liver diseases in Western populations, driven by obesity and insulin resistance. MASH can advance to cirrhosis and hepatocellular carcinoma (HCC), with a rapidly increasing incidence of MASH-related HCC. While lifestyle modification is foundational, pharmacological intervention is gaining importance. This review examines the role of nutrient-stimulated hormone-based therapies (NuSHs), primarily glucagon-like peptide-1 receptor agonists (GLP-1RAs) and newer dual/triple incretin agonists, in managing MASH and potentially preventing and adjunctly treating MASH-associated HCC.
Established Effects of NuSHs in MASH
Clinical trials support the efficacy of GLP-1RAs, such as semaglutide, in resolving MASH without worsening fibrosis, particularly in non-cirrhotic patients. Semaglutide demonstrated MASH resolution in 59–62.9% of patients in phase II/III trials; however, fibrosis improvement in cirrhotic patients remains limited. Newer dual agonists (e.g., tirzepatide, survodutide) and triple agonists (e.g., retatrutide) show histological improvements, including reductions in liver fat and fibrosis markers. Long-term data on clinical outcomes such as progression to cirrhosis, HCC, or mortality are currently not available.
Potential Role in MASH-HCC
Preclinical and observational evidence suggests NuSHs may reduce HCC incidence and tumor burden. This effect is likely due to systemic metabolic improvement rather than direct antitumor action. In murine models, semaglutide reduced HCC incidence by nearly half. Data from bariatric surgery also indicate the preventive role of sustained weight loss. Proposed mechanisms include:
- Amelioration of insulin resistance.
- Reduction of chronic inflammation and oxidative stress.
- Modulation of immune-metabolic pathways that contribute to hepatocarcinogenesis.
NuSHs may also enhance the hepatic microenvironment, potentially improving the response to immunotherapies.
Proposed Immunotherapy Synergy
In MASH-HCC, chronic inflammation and lipotoxicity create an immunosuppressive tumor microenvironment that can limit the effectiveness of immune checkpoint inhibitors. By improving metabolic parameters and reducing hepatic inflammation, NuSHs may improve the liver's condition, making it more receptive to immunotherapy. Additionally, enhanced overall metabolic health may improve patient eligibility for liver transplantation and tolerance to systemic anticancer therapies.
Safety Considerations
NuSHs are generally well-tolerated, but they have side effects. Gastrointestinal symptoms (nausea, diarrhea) are common, particularly with dual/triple agonists. Concerns regarding the risk of medullary thyroid cancer with GLP-1RAs persist, advising caution in at-risk individuals. Sarcopenia is another consideration, especially in older or frail patients, although the ratio of fat-to-lean mass loss is similar to that observed with lifestyle interventions. High-protein diets and resistance exercise are recommended to mitigate muscle loss.
Conclusion
NuSHs, especially GLP-1RAs, represent a therapeutic strategy for treating MASH and preventing MASH-related HCC. Their ability to modify key metabolic and inflammatory drivers of hepatocarcinogenesis supports their potential in early intervention and as adjuncts to existing oncological therapies. Future research needs to focus on prospective trials with oncological endpoints, clarification of immunometabolic mechanisms, and evaluation of long-term safety and cost-effectiveness within integrated MASLD-HCC care pathways.