NuSHs can be a promising therapeutic strategy for preventing MASH-related hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent the most common chronic liver diseases in Western populations, driven largely by obesity and insulin resistance. MASH can progress to cirrhosis and hepatocellular carcinoma (HCC), with the incidence of MASH-related HCC rising rapidly. While lifestyle modification remains foundational, pharmacological intervention is increasingly important. This review explores the emerging role of nutrient-stimulated hormone-based therapies (NuSHs)-primarily glucagon-like peptide-1 receptor agonists (GLP-1RAs) and newer dual/triple incretin agonists-in the management of MASH and the potential prevention and adjunct treatment of MASH-associated HCC.

Established beneficial effects of NuSHs in MASH:

Clinical trials robustly 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, though fibrosis improvement in cirrhotic patients remains limited. Newer dual agonists (e.g., tirzepatide, survodutide) and triple agonists (e.g., retatrutide) show promising histological improvements, including significant reductions in liver fat and fibrosis markers. However, long-term data on hard clinical outcomes-such as progression to cirrhosis, HCC, or mortality-are still lacking.

Future directions: A role for NuSHs in MASH-HCC:

Preclinical and observational evidence suggests NuSHs may reduce HCC incidence and tumor burden, likely through systemic metabolic improvement rather than direct antitumor action. In murine models, semaglutide reduced HCC incidence by nearly half. Bariatric surgery data further underscore the preventive role of sustained weight loss. The proposed mechanisms include amelioration of insulin resistance, reduction of chronic inflammation and oxidative stress, and modulation of immune-metabolic pathways that drive hepatocarcinogenesis. NuSHs may also improve the hepatic microenvironment, potentially enhancing response to immunotherapies.

Proposed immunotherapy synergy as a mechanism of action:

In MASH-HCC, chronic inflammation and lipotoxicity create an immunosuppressive tumor microenvironment that can limit the efficacy of immune checkpoint inhibitors. By improving metabolic parameters and reducing hepatic inflammation, NuSHs may help "recondition" the liver, making it more receptive to immunotherapy. Additionally, improving overall metabolic health may enhance patient eligibility for liver transplantation and tolerance to systemic anticancer therapies.

Safety considerations:

NuSHs are generally well-tolerated but carry notable side effects. Gastrointestinal symptoms (nausea, diarrhea) are common, especially with dual/triple agonists. Concerns about medullary thyroid cancer risk with GLP-1RAs remain unresolved, warranting caution in at-risk individuals. Sarcopenia is another important consideration, particularly in older or frail patients, though the ratio of fat-to-lean mass loss resembles that seen with lifestyle intervention. High-protein diets and resistance exercise are recommended to mitigate muscle loss.

Conclusion:

NuSHs, particularly GLP-1RAs, represent a promising therapeutic strategy not only for treating MASH but also for preventing MASH-related HCC. Their ability to modify key metabolic and inflammatory drivers of hepatocarcinogenesis supports their potential role in early intervention and as adjuncts to existing oncological therapies. Future research must focus on prospective trials with oncological endpoints, clarification of immunometabolic mechanisms, and evaluation of long-term safety and cost-effectiveness in integrated MASLD-HCC care pathways.