What this is
- () is increasingly driven by metabolic dysfunction, alcohol use, and their interplay, leading to a rise in ().
- (GLP-1 RAs) show potential as multifunctional therapeutics against and by targeting shared metabolic pathways.
- This review evaluates the epidemiological links between and , the role of GLP-1 RAs, and the need for further clinical trials.
Essence
- GLP-1 receptor agonists (GLP-1 RAs) are emerging as promising treatments for () and () by addressing shared metabolic dysfunction and inflammation. Their dual action helps reduce cravings for high-calorie foods and alcohol, while improving insulin sensitivity and reducing hepatic fat accumulation.
Key takeaways
- GLP-1 RAs improve metabolic health by reducing appetite and enhancing insulin sensitivity, which are crucial for managing and risk.
- Clinical data suggest GLP-1 RAs are associated with reduced all-cause mortality and lower progression to decompensated cirrhosis among patients with metabolic dysfunction.
- GLP-1 RAs exhibit direct anti-inflammatory and anti-cancer effects, potentially mitigating the progression of liver diseases and .
Caveats
- Most evidence for GLP-1 RAs' anti-tumor effects is from preclinical studies, with limited human data establishing causality.
- Adverse effects, particularly gastrointestinal symptoms, may limit the use of GLP-1 RAs in certain populations.
Definitions
- steatotic liver disease (SLD): A condition characterized by the accumulation of fat in liver cells, often linked to metabolic dysfunction.
- hepatocellular carcinoma (HCC): A primary malignancy of the liver, often associated with chronic liver diseases such as SLD.
- glucagon-like peptide-1 receptor agonists (GLP-1 RAs): Medications that mimic the action of the GLP-1 hormone, enhancing insulin secretion and reducing appetite.
Simplified
Introduction
The global burden of steatotic liver disease (SLD), also known as fatty liver disease, is undergoing a profound epidemiological shift. It is rapidly moving away from viral hepatitis as the sole primary driver of chronic liver morbidity and mortality, and overwhelmingly towards conditions rooted in metabolic dysfunction (Feng et al., 2025; Gines et al., 2025). This shift is driven by the parallel global epidemics of type 2 diabetes mellitus (T2DM) and obesity, which fuel the rise of metabolic dysfunction-associated steatotic liver disease (MASLD) (Danpanichkul et al., 2025; Huang et al., 2025). Now recognized as the most common chronic liver condition globally, MASLD creates a niche for the development of advanced liver pathology, including cirrhosis and hepatocellular carcinoma (HCC) (Huang et al., 2025; Gao et al., 2025). MASLD is estimated to affect over 30% of the worldwide population, with prevalence rates exceeding 70% in individuals with T2DM, underscoring the severity of this metabolic-hepatic nexus (Garg and Zein, 2025).
This metabolic crisis is further complicated by alcohol-associated liver disease (ALD), an aggressive pathology resulting from excessive alcohol consumption. While ALD and MASLD were historically viewed as distinct entities, they share similar histology and some pathological mechanisms, most notably altered metabolic homeostasis in the liver and adipose tissue. More critically, the disease spectrum now includes metabolic dysfunction and alcohol-associated liver disease (MetALD), a recently classified subcategory (Kalligeros et al., 2024; Ho et al., 2025). In MetALD, the co-existence of metabolic risk factors (like obesity and T2DM) and moderate-to-high alcohol consumption creates a synergistic “double-hit” injury that accelerates disease progression and HCC risk significantly more than either factor alone. Collectively, the rising prevalence of MASLD, ALD and MetALD has made these conditions the fastest-growing cause of HCC and among the leading reason for liver transplantation worldwide (Ochoa-Allemant et al., 2025; Harris, 2025).
Furthermore, while chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain established risk factors for HCC, they also induce changes in lipid and glucose homeostasis. This suggests that even viral infections rely on a shared pathophysiological link through altered metabolism and the induction of SLD to drive carcinogenesis (Wang and Zhang, 2023; Wang J. et al., 2024; Nakamura et al., 2025). Given the central role of altered metabolism across virtually all major HCC etiologies, the development of potent pharmacotherapies that target metabolic dysfunction is an urgent priority.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising class of medications to address this underlying metabolic dysregulation that drives SLD. Initially developed for glycemic control in T2DM, GLP-1 RAs act as incretin mimetics by stimulating glucose-dependent insulin secretion and inhibiting glucagon release (Brunton and Wysham, 2020; He X. et al., 2024). Beyond their effects on insulin secretion, accumulating evidence demonstrates that GLP-1 RAs also enhance insulin sensitivity and reduce systemic insulin resistance. More recent studies further highlight that these agents exert both central and peripheral actions, conferring a powerful dual mechanism of action. Centrally, GLP-1 RAs modulate reward pathways to reduce cravings for both high-calorie foods and alcohol (Farokhnia et al., 2025; Jerlhag, 2025; Hendershot et al., 2025), key behavioral drivers of SLD. Peripherally, they improve insulin sensitivity, reduce hepatic lipotoxicity, and attenuate systemic and hepatic inflammation (Jones and Brierley, 2025; Skibicka, 2013). Clinical studies in patients with MASLD have shown that GLP-1 RA therapy is associated with clinically meaningful reductions in progression to metabolic dysfunction-associated steatohepatitis (MASH). Complementary preclinical studies in animal models demonstrate that GLP-1 RAs reduce alcohol craving and alcohol consumption, suggesting potential therapeutic benefit in alcohol use disorder (AUD). These central effects, together with their ability to ameliorate metabolic dysregulation observed in ALD, a condition for which the only established therapeutic options currently remain sustained abstinence or liver transplantation. This review aims to dissect the epidemiological and mechanistic links between altered metabolism and HCC across MASLD, ALD, and viral etiologies, summarize the current therapeutic landscape, and critically evaluate the emerging role of GLP-1 RAs as a strategic intervention for prevention and clinical management across this complex disease spectrum.
Global epidemiology and SLD progression to HCC
HCC is a significant global health threat, ranking as the fourth most common cancer and the second leading cause of cancer-related mortality worldwide (Bray et al., 2024). The global rise in HCC incidence is strongly and disproportionately correlated with the epidemic rise of MASLD (Ma et al., 2024; Shi et al., 2024). Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of MASLD characterized by inflammation and hepatocyte injury, is expected to overtake chronic hepatitis C as the most common indication for liver transplantation (Goldberg et al., 2017; Younossi et al., 2021). Data from the last 2 decades reveal a dramatic increase in HCC attributable to MASH (Karin and Kim, 2025). Alcohol consumption also remains an intractable risk factor, with heavy, long-term use contributing significantly to HCC and accounting for 30% of HCC cases and HCC-specific deaths (Patel and Mueller, 2025). This risk is further compounded in MetALD patients, where the coexisting metabolic syndrome and alcohol consumption establish a uniquely high-risk population driven by synergistic insults (Ochoa-Allemant et al., 2025; Harris, 2025). Regardless of the initial trigger (metabolic stress, alcohol, or virus), the disease typically progresses through a multi-step process: simple steatosis to steatohepatitis (MASH/severe ALD), to cirrhosis and HCC. Intervening at the steatosis or steatohepatitis stage is critical for effective prevention (Jee et al., 2025).
Spectrum of SLD and mechanisms of progression to HCC
HCC predominantly arises in the setting of chronic liver injury, but the specific insults (metabolic excess, alcohol, or viral infection) converge upon a common pathogenic pathway: dysregulated hepatic metabolism. This dysregulated metabolism creates an environment characterized by persistent oxidative stress, chronic inflammation, and altered energy signaling, which collectively drive fibrosis and cellular transformation (Ding et al., 2025; Galasso et al., 2024; Ramaite and Nkadimeng, 2025). Understanding the specific metabolic alterations within each major etiology is key to target the disease with a compound, which can help metabolic homeostasis, such as GLP-1 R analogs (Wang and Lu, 2025; Kanwal et al., 2024; Havranek et al., 2025).
Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD)
The global epidemic of T2DM is inextricably linked to the rising burden of MASLD and HCC. Diabetes affecting over 830 million people, which accounts for 14% of adults 18 years or older worldwide (Danpanichkul et al., 2025). Alarming projections indicate that its prevalence will increase by 25% in 2030 and 50% in 2045 (He KJ. et al., 2024). As the dominant form of the disease, T2DM accounts for over 95% of diabetic patients and is largely attributable to the obesity pandemic (Cusi, 2019; Cusi et al., 2025; Miller et al., 2025). Further, T2DM remains one of the most significant risk factors not only for the development of MASLD but also for the progression of liver fibrosis and the occurrence of liver‐related complications, including HCC (Hosseinkhan et al., 2025; Leith et al., 2024; Riley et al., 2024).
In the context of MASLD and T2DM, altered metabolism is the primary etiology. The root cause is systemic insulin resistance, typically driven by high calorie intake and positive energy balance (excess calories). This chronic caloric excess eventually overwhelms the storage capacity of visceral adipose tissue, leading to adipose tissue failure. Adipose tissue failure forces the spillover of excessive free fatty acids (FFA) into the systemic circulation, causing ectopic fat deposition in non-adipose organs, including the skeletal muscle and, critically, the liver (Dua et al., 2025; Stefan et al., 2025; Tantu et al., 2025). These high circulating FFAs, alongside inflammatory adipokines released by dysfunctional fat tissue, impair insulin signaling and develop systemic insulin resistance. This insulin resistance affects the liver directly, promoting increased de novo lipogenesis and endogenous glucose production, thereby driving both hepatic steatosis and hyperglycemia.
The transition from simple steatosis to advanced liver disease is governed by a multi-parallel hit model against this backdrop of established insulin resistance. Hepatic lipotoxicity creates a pro-inflammatory environment that makes the liver highly susceptible to simultaneous insults, including mitochondrial dysfunction (generating oxidative stress), endoplasmic reticulum stress (Miller et al., 2025; Tantu et al., 2025; Li et al., 2024) and the activation of innate immune cells (kupffer cells) by signals from inflammatory adipokines and endotoxins from the gut (due to gut dysbiosis). These parallel hits drive inflammation, hepatocellular ballooning, and subsequent fibrosis, forming the critical juncture that determines the risk of progression to cirrhosis and HCC.
Current management strategies include foundational interventions like calorie restriction and lifestyle modification, which are shown to improve MASLD treatment outcomes by addressing the root metabolic cause. Furthermore, hypoglycemic agents such as pioglitazone and empagliflozin exhibit beneficial effects on liver tissue outcomes, such as reducing liver fat content and improving liver fibrosis (Jee et al., 2025; Miller et al., 2025; Armandi and Bugianesi, 2024; Isaacs et al., 2025; Pieralice et al., 2025), demonstrating that therapeutic targeting of the metabolic axis is effective.
Alcohol-associated liver disease (ALD)
Excessive alcohol use is a serious health concern globally, and after the brain, the liver sustains the greatest damage. ALD is a major health problem, accounting for 30% of HCC cases (Choi and Kim, 2025). Ninety percent of individuals with excessive alcohol use develop steatosis, the earliest and most common response of the liver to excessive ethanol consumption. Compared to non-drinkers, heavy alcohol consumption has been associated with an 87% increased HCC risk (Chang et al., 2024; Pan et al., 2025).
Central among the many mechanisms proposed to play a role in the development of ALD are impaired metabolic homeostasis and organ crosstalk. Studies have shown that impaired levels of insulin and an increase in insulin resistance lead to increased adipose lipolysis and FFA release into the circulation and their enhanced hepatic uptake, subsequently causing fat accumulation in the liver (Zhong et al., 2012; Wei et al., 2013; Kang et al., 2007; Rasineni et al., 2019a; Boden et al., 2005; Rasineni et al., 2019b). In addition to increased uptake of adipose-derived FFA, several factors contribute to hepatic fat deposition: I) Increased fatty acid synthesis from ethanol-induced metabolism (increased NADH from ethanol metabolism induces fatty acid synthesis); II) Impaired fat transport out of the liver via reduced very-low-density lipoprotein (VLDL) secretion; III) Decreased fatty acid oxidation (Rasineni and Casey, 2012; Osna et al., 2022; Yan et al., 2023). The resulting accumulation of fat in hepatocytes makes the liver susceptible to inflammatory mediators and/or toxic agents, leading to progressive injury, which progresses to alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and cancer (Li et al., 2024; Mackowiak et al., 2024). The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation (Addolorato et al., 2013; Kharbanda et al., 2022; Leko and Leggio, 2024; Adekunle et al., 2023). Any molecule with dual-pronged effects at the central and peripheral organs controlling alcohol craving and alcohol-associated metabolic dysregulation could be a promising therapeutic target to treat alcohol use disorder (AUD) and ALD.
Metabolic dysfunction and alcohol-associated liver disease (MetALD)
The newly recognized subcategory, MetALD, highlights the potent synergy between toxic and metabolic insults. In this recently classified subcategory of liver disease, the co-existence of diet-induced obesity (a metabolic factor) and moderate to high amounts of alcohol consumption creates a double-hit injury. This combination synergistically increases disease progression and HCC risk significantly compared to obesity or alcohol alone (Gratacos-Gines et al., 2025; Marek and Malhi, 2024; Babuta et al., 2024; Schonfeld et al., 2021).
While the individual pathologies of MASLD and ALD are well-established, the specific pathophysiological mechanisms for MetALD development remain under active investigation and are currently considered hypothetical models that require further clinical validation. However, it is proposed that ethanol metabolism directly impairs the hepatic redox state by increasing the NADH/NAD+ ratio. This increased NADH promotes de novo lipogenesis while simultaneously decreasing fatty acid oxidation (Rasineni and Casey, 2012). Beyond the liver, alcohol administration disturbs lipid homeostasis within adipose tissue, triggering a pathological flux of FFA from peripheral fat depots to the liver (Zhong et al., 2012; Wei et al., 2013; Kang et al., 2007; Rasineni et al., 2019a; Boden et al., 2005; Rasineni et al., 2019b). This alcohol-induced steatosis is further compounded by the systemic insulin resistance from obesity, which independently drives an influx of FFA to the liver. Furthermore, the induction of CYP2E1 during chronic alcohol consumption generates massive amounts of ROS, which likely accelerates mitochondrial dysfunction and ER stress, and inflammatory signaling.
This detrimental progression of liver diseases is often driven by a behavioral cycle involving an increased desire, cravings, and high-calorie food intake during and after alcohol drinking episodes and vice versa. Notably, both MASLD and ALD exhibit similar histology and share some pathological mechanisms, reinforcing the idea that altered metabolic homeostasis in the liver and adipose tissue is the final common pathway driving liver injury (Kalligeros et al.; Ho et al., 2025; Marek and Malhi, 2024; Acierno et al., 2025; Leal-Lassalle et al., 2025). However, further studies are warranted to fully delineate the distinct pathophysiology of MetALD development, which is driven by both alcohol and metabolic dysfunction.
Chronic viral hepatitis (HBV and HCV)
While HBV and HCV are primarily known as infectious diseases, their persistent presence induces profound metabolic reprogramming specifically within the host liver cells (hepatocytes), which contributes significantly to the risk of advanced liver disease and HCC (Wang and Zhang, 2023; Suhail et al., 2022; R et al., 2022). This viral-induced dysmetabolism creates a powerful synergy with the underlying drivers of SLD (Schinzari et al., 2015).
HCV infection is strongly associated with systemic insulin resistance and T2DM (El-Zayadi and Anis, 2012). Critically, the virus achieves this by interfering with crucial host signaling pathways within the liver. Specifically, the HCV core protein is known to induce the degradation of insulin receptor substrate (IRS-1 and IRS-2) components, which are vital for proper insulin signaling in hepatocytes (Bose et al., 2012). This interference promotes IR at the cellular level, intensifying the burden of hyperinsulinemia and hyperglycemia on the liver (Kawaguchi et al., 2004; Pazienza et al., 2007).
Furthermore, HCV directly alters hepatic lipid metabolism in a way that mimics and exacerbates hepatic steatosis. The virus promotes the formation and accumulation of lipid droplets (LDs) within hepatocytes, a process essential for its own life cycle, including viral replication and assembly (Kim et al., 2007; Perlemuter et al., 2002). The resulting high levels of intrahepatic fat deposition, coupled with the persistent IR, accelerate the chronic inflammatory and fibrotic processes characteristic of advanced liver disease (Salmon et al., 2012).
HBV, a DNA virus, has also been shown to modulate host metabolic pathways to support its life cycle, with primary effects observed in the liver. Viral proteins, particularly the hepatitis B virus X protein (HBx), act as an important positive regulator for gluconeogenesis (Shin et al., 2011). Further, HBx interacts with cellular machinery to alter lipid homeostasis in the hepatocyte (Yang et al., 2008). HBx can influence the activity of metabolic transcription factors, such as sterol regulatory element-binding proteins (SREBPs), which are key regulators of de novo lipogenesis (Hajjou et al., 2005). This modulation leads to observable steatosis in the liver of some chronic carriers.
Thus, for viral etiologies, the virus acts as the initial trigger, but the resulting metabolic dysregulation and chronic inflammatory state which overlaps significantly with the pathophysiology of MASLD are focused on and ultimately destroy the liver’s tissue architecture, creating the sustained carcinogenic environment (Wang and Zhang, 2023; Suhail et al., 2022; R et al., 2022; Schinzari et al., 2015). Critically, even after successful viral eradication (e.g., sustained virologic response in HCV), residual metabolic damage within the liver can persist, leaving patients with a continued, metabolically-driven risk for HCC (Przybyszewski and Chung, 2023).
Current therapeutic landscape and unmet need
While resmetirom (a THR-β agonist) has recently gained FDA approval for the treatment of MASH (in patients with fibrosis F2-F3), marking the first-ever pharmacological agent for this condition (Liu et al., 2025), there remains no single FDA-approved drug that effectively prevents or reverses the progression of advanced SLD to HCC. The therapeutic approach for HCC remains focused on curative treatments for early stages (resection, ablation, transplantation) or palliative systemic therapies for advanced disease (tyrosine kinase inhibitors [TKIs] and VEGF inhibitors) and immunotherapies (i.e., programmed death 1 [PD-1]/programmed cell death-ligand 1 [PD-L1] inhibitors and anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] antibodies) (Sadagopan et al., 2024; Gord et al., 2024).
Management of the underlying SLDs typically revolves around etiology-specific interventions: lifestyle modifications (diet, exercise, and weight loss) are the cornerstone for MASLD/MASH; complete alcohol cessation (abstinence) is critical for ALD/MetALD; and antivirals are used to suppress viral load in chronic hepatitis (Hailemichael et al., 2024; Sengupta and Mellinger, 2024). However, while lifestyle modification (such as calorie restriction and alcohol abstinence) represents the therapeutic gold standard for MASLD and ALD, achieving and, more importantly, sustaining these intensive behavioral changes over the long term is a significant clinical challenge (Chen et al., 2024; Rajewski et al., 2025). This difficulty in maintaining persistent intervention means that the underlying metabolic dysfunction often continues as the primary driver of advanced liver disease, even in patients who have achieved viral cure or who struggle with these rigorous modifications. This gap defines a critical therapeutic void. There is an urgent need for a pharmacological agent that can specifically and safely correct the shared metabolic pathology, ideally by acting at both central (e.g., controlling appetite and cravings) and peripheral (e.g., improving insulin sensitivity, reducing hepatic fat and inflammation) levels to support and enhance existing behavioral strategies, thereby lowering the risk of advanced liver disease development across metabolic and alcoholic etiologies.
GLP-1 receptor agonists: a multi-functional therapeutic targeting metabolic dysfunction
Glucagon-like peptide-1 (GLP-1), a multifaceted hormone expressed primarily in the intestines and pancreas, mediates physiological and behavioral properties through its receptor, GLP-1 receptors (GLP-1R). The GLP-1R is widely expressed in both central and peripheral tissues, including the brain, heart, and kidney. Importantly, several studies have reported GLP-1R expression on both hepatocytes (liver cells) and adipocytes (fat cells) (Gupta et al., 2010; Zhang et al., 2025; Mahalingam et al., 2023; Vendrell et al., 2011; Muller et al., 2019). However, this remains an area of active debate within the field; while some studies report direct hepatocyte GLP-1R signaling (Shantaram et al., 2025; Hu et al., 2025; Sharma et al., 2011; Gupta et al., 2012; Ding et al., 2006; Wang et al., 2015), others suggest that many hepatic benefits may be indirect, mediated via weight loss, improved insulin sensitivity, and adipose-liver crosstalk (da Silva Lima et al., 2024). Regardless of the specific signaling site, the therapeutic potential of GLP-1 remains significant. Given the rapid degradation of the natural GLP-1 hormone (with a half-life of only ∼2 min), with therapeutic potential motivated the development of long-acting GLP-1 receptor agonists (GLP-1 RAs). These synthetic analogs possess significantly long half-life and are now used clinically. Originally developed as glucose-lowering agents for T2DM (Brunton and Wysham, 2020; He X. et al., 2024), GLP-1 RAs function as incretin mimetics, stimulating insulin release by pancreatic β-cells in a glucose-dependent manner while suppressing glucagon secretion from α-cells (Figure 1).
The mechanism of GLP-1 RAs, however, is now understood to extend far beyond glucose control, offering powerful dual central and peripheral action. Centrally, they manage appetite and cravings by modulating the reward circuitry in the brain, while peripherally, they correct systemic metabolism and reduce hepatic fat accumulation (Jones and Brierley, 2025; Skibicka, 2013; Shantaram et al., 2025; Weghuber et al., 2022; Cusi et al., 2018). This critical dual action is reinforced by data showing that GLP-1R agonists reduce the intake of both high-calorie food and alcohol, which are key drivers of SLDs (Farokhnia et al., 2025; Jerlhag, 2025; Hendershot et al., 2025; Weghuber et al., 2022; Cusi et al., 2018). This multi-functional activity positions GLP-1Rs as a class of medications that target the fundamental metabolic dysregulation driving SLD and the progression to advanced liver injury, thus establishing their role as a leading therapeutic strategy for managing the risk of advanced liver disease and HCC.
Importantly, this mechanistic framework is increasingly supported by large-scale clinical outcome data. Studies involving large patient cohorts demonstrate that GLP-1RA use is associated with a reduced all-cause mortality and decreased progression to decompensated cirrhosis among patients with MASLD/MASH. Furthermore, non-users of GLP-1RAs exhibited more than a twofold higher risk of all-cause mortality compared with GLP-1RA users (Kanwal et al., 2024; Havranek et al., 2025).
Pleiotropic Central and Peripheral Effects of GLP-1 Receptor Agonists (GLP-1RAs). This illustration depicts the integrated mechanisms of GLP-1RAs, highlighting their central modulation of satiety pathways, which suppresses both caloric and alcohol intake, alongside their extensive peripheral system effects. Key systemic actions include enhancing glucose-dependent insulin secretion, restoring insulin sensitivity, and improving systemic metabolic homeostasis.
Systemic and hepatic efficacy: Correcting metabolic derangements and steatosis
As depicted in Figure 1, GLP-1 RAs are highly effective at correcting the core metabolic derangements seen in MASLD/T2DM. Their systemic efficacy is initiated by achieving significant and sustained weight loss and improved insulin sensitivity. This is accomplished centrally by reducing appetite and peripherally by delaying gastric emptying and enhancing glucose-dependent insulin secretion. These potent systemic actions lead to a reduction in visceral adiposity and dramatically improve systemic metabolic control (Weghuber et al., 2022; Cusi et al., 2018; Cai et al., 2025; Mocciaro et al., 2025).
These systemic improvements translate directly to the liver, where GLP-1 RAs provide potent hepatic benefits that extend beyond simple weight loss (Summary of studies evaluating the role of GLP-1RAs in SLDs presented in Table 1). Mechanistically, they directly promote hepatic glucose metabolism and reduce fat accumulation. They reduce de novo lipogenesis by inhibiting transcription factor sterol regulatory element-binding protein 1c (SREBP-1c), which is a master regulator of fatty acid synthesis (Shantaram et al., 2025; Bu et al., 2024). Concurrently, they promote fatty acid β-oxidation by increasing peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional factor regulating genes involved in mitochondrial and peroxisomal fatty acid catabolism (Ding et al., 2006). This crucial dual action of reducing synthesis and increasing catabolism effectively decreases intrahepatic triglyceride content. Furthermore, by improving overall insulin sensitivity, GLP-1RAs decrease the toxic influx of free fatty acids from adipose tissue to the liver, thereby mitigating hepatic lipotoxicity (Wang et al., 2017). Beyond lipid metabolism, the GLP-1 RAs also shown critical anti-inflammatory and antioxidant effects, collectively positioning these GLP-1 RAs as a leading pharmacotherapy for MASLD (Chen et al., 2025; Pasta et al., 2025; Wang L. et al., 2024; Wei et al., 2025). Clinically, this potent effect is demonstrated by agents like semaglutide, which, in phase 2 trials, achieved MASH resolution without worsening fibrosis in a significant percentage of patients (Armstrong et al., 2016; Newsome et al., 2021; Petta et al., 2025; Sanyal et al., 2025; Lawitz et al., 2024; Jara et al., 2025).
Furthermore, liraglutide and semaglutide have both demonstrated anti-fibrotic effects and their use in preclinical models prevents NASH-driven HCC progression (Sanyal et al., 2025; Mantovani et al., 2021). Beyond MASLD, emerging preclinical evidence highlights the therapeutic potential of GLP-1 RAs in ALD and MetALD (Singal and Leggio, 2025). Specifically, our published data confirms that exendin-4, significantly improves ALD pathology by reducing hepatic steatosis, inflammation, and oxidative stress in experimental rats (Mahalingam et al., 2023). In addition to our study, a recent clinical cohort study indicated that GLP-1 RA use was associated with significantly fewer liver-related outcomes. This includes reduced rates of acute decompensated liver failure and alcoholic hepatitis, although, notably, no significant difference was observed in the progression to cirrhosis within the study period (Wickramarachchi et al., 2025).
The central action of GLP-1 receptor agonists is supported by evidence showing that exenatide and semaglutide reduce the intake of high-calorie foods and alcohol, as well as relapse-like drinking in rodent models. These critical effects are mediated through GLP-1R signaling within the mesolimbic reward system, which directly targets key drivers of AUD, ALD, and MetALD. Preclinical and clinical studies have demonstrated that GLP-1RAs reduce both alcohol craving and intake, confirming the direct neurobiological pathway targeted by this drug class (Farokhnia et al., 2025; Jerlhag, 2025; Hendershot et al., 2025; Chuong et al., 2023; Klausen et al., 2022; Patel et al., 2025). This universality even extends to viral hepatitis, as liraglutide has been shown in vitro to directly inhibit HCV replication through an AMPK-dependent mechanism (Lee et al., 2019), reinforcing the drug class’s broad impact on metabolic health critical for diverse liver pathologies. This combined systemic, direct hepatic, anti-addictive, and even anti-viral action establishes GLP-1RAs as a powerful, novel approach to reduce the cumulative toxic insults driving SLD progression across multiple etiologies.
| GLP-1RAs | Animal model/clinical study | Biological actions | Level of evidence | References |
|---|---|---|---|---|
| Exenatide (Ex-4) | Clinical trial | Exenatide decreased alcohol intake in overweight alcohol use disorder (AUD) patients | Clinical | [Klausen et al. (2022)] |
| Dulaglutide | Clinical study | Dulaglutide treatment decreased alcohol intake in smoking AUD patients | Clinical | [Probst et al. (2023)] |
| Semaglutide and tirzepatide | Clinical study | Semaglutide lowered binge drinking, alcohol use disorder identification test (AUDIT) scores, and self-reported alcohol intake in overweight individuals with high alcohol intake | Clinical | () [Quddos et al., 2023] |
| Exendin-4 | Lieber-DeCarli ethanol-diet fed rat | Exendin-4 reduces hepatic steatosis in Lieber-DeCarli ethanol-diet fed animals by improving insulin signaling and fat metabolism | Clinical | [Mahalingam et al. (2023)] |
| GLP-1RAs | Clinical study | GLP-1R agonist treatment reduces the desire to consume alcohol, interest in alcohol, and alcohol consumption in patients treated for obesity or type 2 diabetes | Clinical | [Bremmer and Hendershot (2024)] |
| GLP-1RAs | Clinical and experimental animal study | GLP-1RAs reduce alcohol consumption | Clinical | [Farokhnia et al. (2025)] |
| Semaglutide | Clinical trial | Low-dose semaglutide over 9 weeks of treatment can reduce alcohol craving and some drinking outcomes | Clinical | [Hendershot et al. (2025)] |
| Liraglutide | HepG2 cells | HepG2 cells decreased proliferation after liraglutide treatment without altering oxidative stress levels. Liraglutide was able to induce autophagy and senescence through the increase of TGF-β1, which possibly explains the growth decrease | In vitro | [Krause et al. (2017)] |
| Exenatide (Ex-4) | Obese DEN-treated mice | Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells | In vivo | [Zhou et al. (2017)] |
| Exenatide (Ex-4) | HepG2 cells | Exenatide has a potent anti-proliferative activity via mTOR modulation using HepG2 cells | In vitro | [Krause et al. (2019)] |
| Liraglutide | Mouse | Liraglutide prevented the progression of hepatocellular carcinoma in a mouse model of Nonalcoholic Steatohepatitis | In vivo | [Kojima et al. (2020)] |
| Liraglutide | Mouse | Liraglutide activates natural killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma | In vivo | [Lu et al. (2021)] |
| Semaglutide | GAN-DIO‐NASH mice | Semaglutide prevents NASH-driven HCC progression in a metabolic translational preclinical model | In vivo | [Mollerhoj et al. (2022)] |
| Liraglutide | HFD mice | Liraglutide ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor α-mediated autophagy pathway | In vivo | [Yu et al. (2023)] |
| Semaglutide | GAN diet-induced obese | Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC. | In vivo | [Hansen et al. (2023)] |
| Semaglutide | HFD-induced obese mice | Semaglutide treatment decelerates the progression of liver cancer by inducing the expression of ITGAV, LAMC1, FABP5, and LPL in the adipose tissue of obese mice | In vivo | [Liu et al. (2024)] |
| GLP-1R agonists | Meta-analysis | GLP-1 RAs provide protective benefits against HCC in T2DM patients compared to insulin or no GLP-1 RAs, but not significantly over other antidiabetic medications | Meta-analysis | [Shabil et al. (2024)] |
| GLP-1R agonists | Meta-analysis | GLP-1RAs were associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC, and LT, in MASLD cirrhosis patients with type 2 diabetes | Meta-analysis | [Elsaid et al. (2024)] |
| Semaglutide | MASH or Advanced liver fibrosis | Semaglutide at a dose of 2.4 mg improved liver histologic results in patients with MASH or advanced liver fibrosis | Clinical | [Sanyal et al. (2025)] |
| GLP-1R agonists | Meta-analysis | Meta-analysis provides evidence for the effectiveness of GLP-1 receptor agonists in managing MAFLD, with dual GLP-1/GIP agonists demonstrating superior hepatic benefits | Meta-analysis | [Tamilwanan et al. (2025)] |
Anti-inflammatory and direct tumor-suppressive signaling
GLP-1 receptor agonists exert direct modulatory effects on some molecular pathways implicated in HCC initiation and progression, effects that may occur independently of reducing visceral adipose tissue and pro-inflammatory adipokine release from adipose tissue. Recognizing that chronic inflammation is a major driver of SLD progression and hepatocarcinogenesis, GLP-1 RAs demonstrate potent anti-inflammatory and tumor-suppressive actions (Que et al., 2019; Wan and Sun, 2019; Kojima et al., 2020; Zhao et al., 2014). The core tumor-suppressive mechanism involves activating AMP-activated protein kinase (AMPK), a key cellular energy sensor. AMPK activation subsequently inhibits the mTORC pathway (a major regulator of cell growth and proliferation) and promotes cell cycle arrest by stabilizing p53 and the p21/p27 inhibitors (Hardie, 2013; Hardie et al., 2012). This direct molecular targeting underpins their utility as specific anti-cancer agents.
Preclinical studies validate these direct anti-tumor effects across different agents: Liraglutide, for instance, demonstrates potent anti-cancer activity by suppressing HCC progression in mouse models, crucially exhibiting an anti-inflammatory effect by inhibiting the IL-6/STAT3 signaling pathway (Kojima et al., 2020; Lu et al., 2021). This action enhances antitumor activity via NK-mediated cytotoxicity, while liraglutide also induces autophagy and senescence in HepG2 cells via TGF-β modulation (Chen-Liaw et al., 2017; Krause et al., 2017). Similarly, exenatide-4 inhibits hepatocarcinogenesis independent of obesity and MASH resolution, acting through the cAMP-PKA-EGFR-STAT3 axis and mTOR modulation to suppress proliferation and reduce HCC multiplicity (Zhou et al., 2017). Furthermore, semaglutide prevents MASLD/MASH-driven HCC progression in metabolic preclinical models, partly by correcting adipokine imbalances (low adiponectin, high leptin) associated with insulin resistance, which removes a key chronic inflammatory and pro-oncogenic signal linked to the disease (Kojima et al., 2020).
It is important to note that most of the evidence supporting the anti-tumor efficacy of GLP-1 RAs is derived from preclinical studies, including in vitro studies and animal experiments demonstrating reduced proliferation of the cancer cells, enhanced apoptosis, and modulation of oncogenic signaling pathways (Arvanitakis et al., 2022). In humans, current data remain largely associative, based on observational and epidemiological studies reporting lower HCC incidence among GLP-1 RA users compared to placebo. However, there are no randomized controlled trials with HCC incidence as a primary endpoint, and the observed associations may be influenced by confounding factors such as weight reduction, improved glycemic control, and concomitant use of statins or other hepatoprotective agents. These limitations underscore the need for prospective, well-designed clinical trials to establish causality and clarify the direct role of GLP-1 RAs in HCC prevention.
These systemic and direct molecular effects, particularly the potent anti-inflammatory actions and metabolic correction, are highly relevant to mitigating the progression of both ALD and MetALD. By resolving the underlying steatosis and reducing the chronic inflammatory burden, GLP-1 RAs reinforce their potential as powerful anticancer agents across the full spectrum of SLD. However, further preclinical studies, especially those focusing on ALD and MetALD models, and prospective clinical trials are necessary to fully translate these promising anticancer benefits to human patients.
Tolerability and safety profile of GLP-1 receptor agonists
GLP-1 receptor agonists are generally well tolerated; however, gastrointestinal adverse effects such as nausea, vomiting, and diarrhea are the most frequently reported, particularly during the initial treatment phase (Wilding et al., 2021; Wharton et al., 2022; Jastreboff et al., 2022; Ghusn and Hurtado, 2024). These symptoms are typically transient but may lead to treatment discontinuation in approximately 5%–10% of patients. Less frequent but clinically relevant risks include pancreatitis and gallbladder disease, such as cholelithiasis and cholecystitis (Sodhi et al., 2023; He et al., 2022). Although a causal association with acute pancreatitis remains debated, observational studies suggest a higher incidence compared with placebo (Nieto et al., 2025; Storgaard et al., 2017; Pinto et al., 2019). GLP-1 RAs also delay gastric emptying, which contributes to satiety but may exacerbate symptoms in patients with pre-existing gastroparesis (He et al., 2022; Jalleh et al., 2024).
Additionally, weight loss with GLP-1 RAs is accompanied by reductions in lean mass, with skeletal muscle accounting for approximately 15%–40% of total weight loss (Pandey et al., 2024; Sargeant et al., 2019), raising significant concerns regarding sarcopenia, particularly in older or frail individuals with cirrhosis. Caution is advised in patients with a history of severe gastrointestinal disorders or pancreatitis. While these adverse effects do not typically outweigh the substantial metabolic benefits, they may limit use in specific patient populations, necessitating careful dose titration and clinical monitoring. Also, side effects for GLP-1RAs in liver disease patients often include gastrointestinal issues, which can be managed with lower initial doses.
Conclusion and future directions
The data strongly supports that SLD, is fueled by common pathways of altered metabolism and chronic inflammation, which are the central precipitating factors for HCC development across MASLD, ALD, and to some extent, chronic viral etiologies. Given this unifying pathophysiology, GLP-1 RAs, with their powerful ability to act both centrally (controlling appetite and cravings) and peripherally (correcting systemic metabolic dysfunction, resolving hepatic steatosis and inflammation), to exert direct anti-carcinogenic effects, represent a truly multi-functional therapeutic tool. Their ability to simultaneously address metabolic risk factors, inflammation, and cellular proliferation positions them as one of the most promising drug classes for interrupting SLD progression (Figure 2).
The encouraging efficacy of GLP-1 RAs in reversing MASH histology in clinical trials and reducing HCC risk in epidemiological studies provides a powerful mandate for further investigation. However, the next phase of translational research must now broaden its scope. Specifically, future work should prioritize conducting specific animal studies to validate the hypothesized anti-fibrotic and anti-cancer effects of GLP-1 RAs in ALD and MetALD models.
Crucially, more clinical studies are required to definitively establish the efficacy and safety of GLP-1 RAs for the treatment of ALD and MetALD. These trials must move beyond MASLD and include populations with significant alcohol exposure and mixed etiologies. Furthermore, research is critical to investigate the impact of GLP-1 RAs on HCC risk in patients with significant metabolic risk factors, including those who have achieved viral suppression from chronic viral hepatitis. Ultimately, the definitive role of GLP-1 RAs as an anticancer agent pivot on launching large-scale, randomized controlled trials focused explicitly on the primary prevention of HCC in high-risk patients with advanced SLD of all major etiologies.
Mechanistic overview of GLP-1 Receptor agonists (GLP-1 RAs) in ALD, MASLD and MetALD. This schematic illustrates the proposed mechanisms by which GLP-1RAs can exert beneficial effects across the spectrum of steatotic liver diseases, including alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction and alcohol-associated liver disease (MetALD).