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Peptides for NAFLD/NASH Research

Non-alcoholic fatty liver disease (NAFLD) — now formally renamed metabolic dysfunction-associated steatotic liver disease (MASLD) — affects roughly 38% of the global adult population [1].

Non-alcoholic fatty liver disease (NAFLD) — now formally renamed metabolic dysfunction-associated steatotic liver disease (MASLD) — affects roughly 38% of the global adult population [1]. Its more aggressive form, non-alcoholic steatohepatitis (NASH/MASH), involves active liver inflammation and can progress to fibrosis, cirrhosis, and liver failure. Until March 2024, there were zero FDA-approved treatments for NASH. That changed with resmetirom (Rezdiffra), and several peptide-based therapies are now reshaping the treatment pipeline.

This guide reviews the peptides with the strongest research backing for fatty liver disease, from GLP-1 receptor agonists with Phase 3 human trial data to investigational compounds still in animal studies.

Table of Contents

Understanding NAFLD/NASH and Why Peptides Matter

NAFLD exists on a spectrum. Simple steatosis — fat accumulation in the liver without significant inflammation — affects about 1 in 3 adults worldwide. In roughly 7-14% of those people, the disease progresses to NASH, where inflammation actively damages liver cells and drives fibrosis (scarring) [2].

The numbers are staggering. Global NAFLD prevalence jumped from 25.3% in 1990-2006 to 38% in 2016-2019 — a 50% increase in just two decades [1]. Over 90% of obese individuals develop some degree of fatty liver, as do 60% of people with diabetes. By 2040, projections suggest MASLD will affect more than 55% of the global adult population.

NASH now ranks as one of the fastest-growing indications for liver transplant in the United States. And the cardiovascular risk is substantial — heart disease, not liver failure, is the most common cause of death among NAFLD patients [3].

This is where peptides enter the picture. Several peptide-based drugs target the overlapping metabolic pathways — insulin resistance, lipid metabolism, inflammation, and fibrosis — that drive fatty liver progression. The most advanced of these are GLP-1 receptor agonists, with semaglutide and tirzepatide both producing landmark trial results.

For a broader look at peptides that support liver function, see our guide on Best Peptides for Liver Health.

Semaglutide: The Phase 3 Frontrunner

Semaglutide is a GLP-1 receptor agonist already well-known for its effects on blood sugar control and weight loss (marketed as Ozempic and Wegovy). Its role in NASH treatment has been one of the most closely watched developments in hepatology.

The ESSENCE Trial

The ESSENCE trial is an ongoing Phase 3, multicenter, randomized, double-blind, placebo-controlled study involving 1,197 patients with biopsy-confirmed MASH and stage 2 or 3 fibrosis. Patients received once-weekly subcutaneous semaglutide at 2.4 mg or placebo for up to 240 weeks. Results from the planned interim analysis at week 72 were published in the New England Journal of Medicine in April 2025 [4].

Both primary endpoints were met:

EndpointSemaglutide 2.4 mgPlaceboDifference
MASH resolution without worsening fibrosis62.9%34.3%28.7 percentage points (P<0.001)
Fibrosis reduction without worsening MASH36.8%22.4%14.4 percentage points (P<0.001)
Combined resolution + fibrosis improvement32.7%16.1%16.5 percentage points (P<0.001)
Mean body weight change-10.5%-2.0%—

The fibrosis finding matters enormously. Improving fibrosis is the single most important factor for long-term prognosis in NASH patients, and earlier semaglutide trials had failed to show statistically significant fibrosis improvement. The ESSENCE data changed that [4].

FDA Approval for MASH

In August 2025, the FDA granted accelerated approval for semaglutide (Wegovy) in adults with biopsy-confirmed MASH and moderate-to-advanced fibrosis — making it the first GLP-1 therapy authorized for this indication [5].

Earlier Phase 2 Data

A 72-week Phase 2 trial had previously shown that once-daily semaglutide at 0.4 mg produced NASH resolution in 59% of patients versus 17% on placebo (P<0.001). However, fibrosis improvement in that trial was 43% versus 33% — not statistically significant [6].

How It Works in Fatty Liver

Semaglutide reduces liver fat through multiple pathways. Weight loss (averaging 10.5% in ESSENCE) plays a major role, since visceral fat drives hepatic steatosis. But GLP-1 receptors also appear to act directly on hepatocytes, reducing de novo lipogenesis (new fat production in the liver), increasing fatty acid oxidation, and dampening the inflammatory signals that push steatosis toward NASH [7].

The most common side effects are gastrointestinal — nausea (36.3%), diarrhea (26.9%), constipation (22.3%), and vomiting (18.6%) [4]. Part 2 of the ESSENCE trial continues through 2029, tracking hard clinical outcomes like progression to cirrhosis.

If you're interested in how semaglutide compares with other weight-loss peptides, see our Best Peptides for Fat Loss guide.

Tirzepatide: Dual-Receptor Results

Tirzepatide activates both GIP and GLP-1 receptors — a dual mechanism that appears to produce even more pronounced metabolic effects than GLP-1 agonism alone.

The SYNERGY-NASH Trial

The Phase 2 SYNERGY-NASH trial enrolled 190 patients with biopsy-proven MASH and stage 2-3 fibrosis. Patients received once-weekly subcutaneous tirzepatide at 5, 10, or 15 mg, or placebo for 52 weeks. Results were published in the New England Journal of Medicine in June 2024 [8].

DoseMASH Resolution (no worsening fibrosis)Fibrosis Improvement (no worsening MASH)Weight Change
Placebo13.2%32.8%-0.8%
5 mg51.8%59.1%-10.7%
10 mg62.8%53.3%-13.3%
15 mg73.3%54.2%-15.6%

At the highest dose, nearly three-quarters of patients achieved MASH resolution. A 2025 post hoc analysis published in JHEP Reports confirmed these benefits were consistent across subgroups defined by demographics, histology, biomarkers, and imaging [9].

The safety profile was similar to what's been observed in tirzepatide's diabetes and obesity trials (SURMOUNT and SURPASS). Gastrointestinal side effects were the most common, and 96% were mild or moderate.

Larger Phase 3 trials are underway. Eli Lilly is working with regulators on next steps toward a MASH indication.

Liraglutide: The Earlier GLP-1 Evidence

Liraglutide was the first GLP-1 receptor agonist studied specifically for NASH, and it laid the groundwork for the semaglutide and tirzepatide programs.

The LEAN Trial

The LEAN trial (Liraglutide Efficacy and Action in NASH) was a 48-week study of liraglutide 1.8 mg daily in patients with biopsy-confirmed NASH. NASH resolution without worsening fibrosis occurred in 39% of liraglutide-treated patients versus 9% on placebo [10].

The Lira-NAFLD Study

In 68 patients with type 2 diabetes and NAFLD, six months of liraglutide 1.2 mg daily produced a 31% relative reduction in liver fat content measured by proton magnetic resonance spectroscopy (P<0.0001). This reduction correlated strongly with weight loss [11].

Limitations

Meta-analyses of pooled liraglutide data for NAFLD have shown mixed results, partly because studies varied in dose, duration, and patient populations. One meta-analysis found no significant difference versus placebo in hepatic fat content across five trials with 371 patients [12]. The stronger evidence has come from higher doses (1.8 mg) given for longer durations.

Liraglutide's effects appear to extend beyond weight loss alone. One study found improvements in liver function and fibrosis markers regardless of BMI change, suggesting some direct hepatic benefit from GLP-1 receptor activation [13].

For more on how these drugs compare in metabolic contexts, see our guide on Peptides for Metabolic Syndrome.

BPC-157: Preclinical Liver Protection

BPC-157 (Body Protection Compound-157) is a 15-amino acid peptide originally isolated from human gastric juice. Unlike the GLP-1 drugs above, BPC-157 has no large human trial data for liver disease. Its evidence comes entirely from animal models — but those results are notable.

Animal Study Findings

In 1993, researchers tested BPC-157 in three rat models of liver injury: bile duct and hepatic artery ligation, restraint stress, and carbon tetrachloride (CCl4) administration. BPC-157, given either orally or by injection, significantly prevented liver necrosis and fatty changes in all three models. Reference drugs like bromocriptine, amantadine, and somatostatin had little or no protective effect [14].

Rats given BPC-157 before CCl4 exposure showed significantly lower bilirubin and liver enzyme levels. The peptide also reduced fat accumulation in hepatocytes and the extent of coagulative necrosis [14].

More recent work has shown BPC-157 protects against ischemia-reperfusion liver injury — damage that occurs when blood flow is cut off and then restored. In these studies, BPC-157-treated animals had significantly less sinusoidal dilation, fewer necrotic cells, and lower inflammatory cell infiltration. Antioxidant activity was significantly higher in liver tissue of treated animals [15].

Proposed Mechanisms

BPC-157's liver-protective effects appear to involve several pathways:

  • Nitric oxide (NO) modulation: BPC-157 interacts with the eNOS pathway, stabilizing NO production during injury [16]
  • Antioxidant upregulation: The peptide increases expression of heme oxygenase-1 (HO-1), heat shock proteins, and glutathione-related enzymes [17]
  • Angiogenesis: BPC-157 upregulates VEGFR2, promoting new blood vessel growth to support tissue repair [17]
  • Anti-inflammatory effects: Reduced levels of pro-inflammatory cytokines like IL-6 and TNF-alpha [17]

What's Missing

No human study has tested BPC-157 for NAFLD, NASH, or any liver condition. The FDA classified BPC-157 as a Category 2 bulk drug substance in 2023, citing safety concerns and insufficient human data. Compounding pharmacies can no longer legally produce it for human use in the United States [18].

For the full picture on BPC-157's research profile across all organ systems, see our BPC-157 Complete Scientific Guide.

CJC-1295 and the Growth Hormone Connection

CJC-1295 is a synthetic analog of growth hormone-releasing hormone (GHRH) that sustainably increases growth hormone (GH) and IGF-1 levels. No published study has tested CJC-1295 directly for NAFLD — but the connection between growth hormone deficiency and fatty liver disease is well-established.

Adults with growth hormone deficiency develop NAFLD at significantly higher rates. The metabolic picture of adult GH deficiency — increased visceral fat, insulin resistance, abnormal lipid profiles — overlaps almost perfectly with the conditions that drive NASH [19].

In mouse models, disrupting GH signaling in hepatocytes leads directly to hepatic steatosis. GH appears to suppress de novo lipogenesis (new fat creation in the liver) and increase beta-oxidation (fat burning), and these effects are at least partly independent of IGF-1 [20].

Human Trial: GH for NAFLD

A 2023 randomized, double-blind, placebo-controlled trial tested daily GH injections in 53 overweight or obese adults with NAFLD (no diabetes). After six months, GH treatment significantly reduced liver fat content measured by proton MRS, without worsening blood sugar [21].

In GH-deficient patients, replacement therapy has shown even clearer results — six months of treatment significantly reduced liver enzymes and improved liver histology [22].

The CJC-1295 Connection

CJC-1295 increases GH secretion 2-10 fold and IGF-1 levels 1.5-3 fold after a single injection, with effects lasting 6-11 days [23]. In theory, this sustained GH elevation could deliver some of the liver benefits seen with direct GH replacement. But no one has studied it specifically for NAFLD, and CJC-1295's clinical development was discontinued after a trial participant died from what was believed to be unrelated coronary artery disease [24].

For more on growth hormone secretagogues, see our Ipamorelin profile, which is often combined with CJC-1295 in the Peptide Stacking Guide.

Other Peptides Under Investigation

Metabolitin

A newly identified peptide hormone derived from osteocalcin, metabolitin inhibits fat absorption in the intestines and significantly improved NAFLD in animal models. Its receptor, GPRC6A, represents a new therapeutic target [25].

Kisspeptin

Mouse studies show kisspeptin protects against fatty liver, NASH, and fibrosis through its receptor KISS1R. Rutgers researchers described a "powerful relationship between kisspeptin and the reduction of liver fat and fibrosis" [26].

AWRK6

This synthetic peptide, developed from the antimicrobial peptide Dybowskin-2CDYa, acts as a novel GLP-1 receptor agonist candidate. In animal models, AWRK6 improved both lipid and glucose metabolism in MASLD [27].

Peptide YY (PYY)

PYY reduces food intake and induces weight loss through the gut-brain axis. Mice lacking PYY become hyperphagic and obese. Beyond appetite regulation, PYY may improve pancreatic beta-cell survival and function, which connects to the insulin resistance driving NAFLD [28].

Peptide Comparison Table

PeptideEvidence LevelKey NASH FindingFibrosis ImpactFDA Status for NASH
SemaglutidePhase 3 (n=1,197)62.9% MASH resolution36.8% improvementAccelerated approval (Aug 2025)
TirzepatidePhase 2 (n=190)73.3% MASH resolution (15 mg)54.2% improvement (15 mg)Phase 3 underway
LiraglutidePhase 2 (n=52)39% NASH resolutionNot significantNot pursued for NASH
BPC-157Preclinical onlyPrevented liver necrosis/steatosis in ratsNot studiedCategory 2 (banned from compounding)
CJC-1295Indirect (GH data)GH replacement reduced liver fatNot studied directlyDevelopment discontinued
Resmetirom (non-peptide)Phase 3 (n=888)First FDA-approved NASH drugSignificant improvementFull approval (March 2024)

Frequently Asked Questions

What is the difference between NAFLD and NASH?

NAFLD is the umbrella term for fat accumulation in the liver not caused by alcohol. Simple steatosis (fat without inflammation) is the milder form. NASH is the inflammatory subtype where fat triggers liver cell damage, inflammation, and fibrosis. Only NASH puts you at significant risk for cirrhosis. The medical community has renamed these conditions MASLD and MASH, respectively, since 2023.

Which peptide has the strongest evidence for fatty liver?

Semaglutide, by a wide margin. It has Phase 3 data from 1,197 patients showing statistically significant improvements in both NASH resolution and fibrosis, and received FDA accelerated approval for MASH in August 2025. Tirzepatide's Phase 2 data is also strong, with Phase 3 studies in progress.

Can BPC-157 treat fatty liver disease?

No human studies have tested BPC-157 for NAFLD or NASH. Animal research shows it protects against several types of liver injury, but these findings have not been confirmed in people. The FDA has restricted BPC-157 from compounding pharmacies, and it remains unapproved for any human use.

Are GLP-1 drugs only effective because of weight loss?

Weight loss is a major component — semaglutide patients in ESSENCE lost an average of 10.5% body weight. But GLP-1 receptor agonists also appear to act directly on liver cells, reducing fat production and inflammation through pathways that go beyond weight reduction alone. Some liraglutide studies found liver improvements independent of BMI changes.

What was the first FDA-approved drug for NASH?

Resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist made by Madrigal Pharmaceuticals, received accelerated approval in March 2024. It is not a peptide. Its annual wholesale cost is approximately $47,400. Semaglutide became the first GLP-1 therapy approved for MASH in August 2025.

Can peptides reverse liver fibrosis?

The ESSENCE trial showed semaglutide improved fibrosis in 36.8% of patients versus 22.4% on placebo, and tirzepatide showed fibrosis improvement rates of 54-59% across doses. These are the most promising fibrosis results from peptide therapies to date. However, "improvement" typically means a one-stage reduction on the fibrosis scale — complete reversal of advanced fibrosis has not been demonstrated.

Is NAFLD reversible?

Simple steatosis is often reversible with weight loss, dietary changes, and exercise. A sustained 7-10% reduction in body weight can significantly reduce liver fat. NASH with established fibrosis is harder to reverse, though the GLP-1 agonist data shows it is possible in a meaningful percentage of patients with appropriate treatment.

The Bottom Line

The peptide research pipeline for NAFLD/NASH has produced its first real success stories. Semaglutide's ESSENCE trial data — 62.9% MASH resolution and statistically significant fibrosis improvement — led to FDA approval and validated the GLP-1 approach. Tirzepatide's dual-receptor mechanism produced even higher resolution rates in Phase 2, and Phase 3 results are eagerly anticipated.

These drugs work. They also come with significant gastrointestinal side effects and high costs. And they don't work for everyone — roughly 37% of semaglutide patients did not achieve MASH resolution.

Earlier-stage peptides like BPC-157 show liver-protective properties in animal models but lack the human data needed to draw clinical conclusions. The gap between rat studies and bedside reality remains wide, and the FDA's compounding restrictions on BPC-157 reflect that gap.

For the estimated 38% of adults living with some degree of fatty liver, the message is cautiously optimistic: the first generation of effective peptide-based treatments has arrived, and a more diverse pipeline is building behind it. If you're concerned about fatty liver disease, a conversation with your doctor about GLP-1 agonists — alongside the foundational interventions of weight management, diet, and exercise — is a reasonable place to start.

References

  1. Dong B, et al. Global burden of adult non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Translational Gastroenterology and Hepatology. 2024. PMC

  2. Younossi ZM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-1347. PubMed

  3. Estimated Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease in US Adults, 2020 to 2050. JAMA Network Open. 2025. PMC

  4. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. NEJM

  5. ESSENCE phase 3 trial of semaglutide showed significant improvements at 72 weeks in adults with MASH, published in NEJM. Novo Nordisk Press Release. PR Newswire

  6. Newsome PN, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. NEJM

  7. GLP-1 receptor agonists improve metabolic dysfunction-associated steatotic liver disease outcomes. Scientific Reports. 2025. Nature

  8. Loomba R, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024;391:299-310. NEJM

  9. Consistent improvements in liver histology across subgroups in a post hoc analysis of the SYNERGY-NASH trial with tirzepatide. JHEP Reports. 2025. JHEP Reports

  10. Armstrong MJ, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-690. PubMed

  11. Petit JM, et al. Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study. J Clin Endocrinol Metab. 2017;102(2):407-415. Oxford Academic

  12. Liraglutide in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. PubMed. 2020. PubMed

  13. Determining whether the effect of liraglutide on non-alcoholic fatty liver disease depends on reductions in the body mass index. PMC. 2020. PMC

  14. Hepatoprotective effect of BPC 157, a 15-amino acid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl4 administration. Life Sciences. 1993;53(18):PL291-296. PubMed

  15. Protective Effects of BPC 157 on Liver, Kidney, and Lung Distant Organ Damage in Rats with Experimental Lower-Extremity Ischemia-Reperfusion Injury. PMC. 2025. PMC

  16. Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway. Scientific Reports. 2020. Nature

  17. Multifunctionality and Possible Medical Application of the BPC 157 Peptide — Literature and Patent Review. Pharmaceuticals. 2025;18(2):185. MDPI

  18. FDA Category 2 Classification of BPC-157. Regulatory Alert. Holt Law

  19. Growth Hormone and Insulin-Like Growth Factor 1 Regulation of Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab. 2022;107(7):1812-1824. Oxford Academic

  20. GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner. J Endocrinol. 2020. PubMed

  21. Growth Hormone Administration Improves Nonalcoholic Fatty Liver Disease in Overweight/Obesity: A Randomized Trial. J Clin Endocrinol Metab. 2023. PMC

  22. Long-term effects of growth hormone replacement therapy on liver function in adult patients with growth hormone deficiency. Growth Horm IGF Res. 2014. ScienceDirect

  23. Teichman SL, et al. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799-805. PubMed

  24. CJC-1295. Wikipedia. Wikipedia

  25. Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A. J Hepatol. 2020. ScienceDirect

  26. Kisspeptin: A New Drug to Treat Liver Disease? Rutgers University. Rutgers

  27. Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease. PMC. 2024. PMC

  28. Gastrointestinal peptides and nonalcoholic fatty liver disease. World J Gastroenterol. 2019. PubMed