image: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common chronic liver disease in the Western world, driven by obesity, insulin resistance, and systemic inflammation. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), can culminate in cirrhosis and hepatocellular carcinoma (HCC). While lifestyle modification remains central to MASLD management, there is growing interest in pharmacological interventions, particularly nutrient-stimulated hormone-based therapies (NuSHs), such as GLP-1 receptor agonists. NuSHs exert metabolic and anti-inflammatory effects primarily via weight loss and improved insulin sensitivity. Emerging clinical data support their efficacy in resolving MASH without worsening fibrosis. However, benefits in cirrhotic patients are less evident, suggesting greater utility in early intervention. Observational studies and clinical trials suggest a reduction in liver-related morbidity with GLP-1 receptor agonist use, though fibrosis regression remains inconsistent. Preclinical models indicate that NuSHs may also reduce MASH-related HCC incidence and tumor burden, likely through systemic metabolic improvements rather than direct antineoplastic action. Observational human data following bariatric surgery reinforce this link, suggesting that weight loss itself plays a key preventive role. Herein, we propose that NuSHs are promising candidates for MASH-related HCC prevention. We provide mechanistic suggestions for how this may occur. Furthermore, incorporating NuSHs into the post-locoregional treatment pathway for HCC may delay the need for systemic anti-cancer therapies, improve immunotherapy synergy and transplant eligibility, and even slow disease progression through reversal of carcinogenic drivers. Future studies are needed to target oncological endpoints and clarify immunometabolic mechanisms to guide the integration of NuSHs into MASLD treatment algorithms.
Credit: Richard Phillips
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.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00303
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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Journal
Journal of Clinical and Translational Hepatology
Article Title
Nutrient-stimulated Hormone-based Therapies: A New Frontier in the Prevention and Management of MASH-associated Hepatocellular Carcinoma
Article Publication Date
22-Oct-2025