A single protein that tells your liver to burn fat, tells your brain to curb sugar cravings, and tells inflamed tissues to heal might just be the future of metabolic medicine.
For decades, the medical community has watched helplessly as non-alcoholic steatohepatitis (NASH)—the most severe form of fatty liver disease—silently reached epidemic proportions. Affecting millions worldwide, this complex condition begins with simple fat accumulation in the liver but can progress to inflammation, fibrosis, cirrhosis, and ultimately liver failure or cancer. The absence of effective treatments has transformed NASH into a rapidly growing cause of liver-related mortality globally. However, recent breakthroughs focusing on a naturally occurring protein called Fibroblast Growth Factor 21 (FGF21) are generating unprecedented excitement in the scientific community. This article explores how targeting FGF21 represents a revolutionary multi-pronged approach that could potentially transform NASH treatment.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, represents a spectrum of chronic liver conditions where more than 5% of hepatocytes develop fat accumulation (steatosis) without significant alcohol consumption. This condition is associated with at least one cardiometabolic risk factor such as overweight, obesity, or insulin resistance 1 2 .
NASH (now also termed metabolic dysfunction-associated steatohepatitis or MASH) represents the progressive form of this disease, characterized histologically by the presence of steatosis, lobular inflammation, and hepatocyte ballooning, with or without fibrosis 1 . This inflammatory, necrotic form can advance to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma 1 2 .
The "multiple-hit" hypothesis is currently the most widely accepted theory explaining NASH pathogenesis, incorporating factors including insulin resistance, adipose tissue hormones, gut microbiota, nutritional factors, and genetic influences 1 2 . This complexity has made developing effective treatments exceptionally challenging.
Until recently, lifestyle interventions remained the cornerstone of NASH management. The 2024 approval of Resmetirom, a THRβ agonist, marked a significant milestone as the first FDA-approved medication for non-cirrhotic adult MASH patients with mild to advanced liver fibrosis 1 2 . However, limitations remain regarding long-term safety data and efficacy in patients with advanced cirrhosis 1 . The heterogeneous nature of NASH means single-target medications likely cannot address all patient needs, necessitating diverse therapeutic approaches for different pathogenic causes and disease stages 1 .
NASH affects millions worldwide and is a rapidly growing cause of liver-related mortality.
Fibroblast Growth Factor 21 (FGF21) is an atypical member of the fibroblast growth factor family, functioning as a metabolic hormone with distinct endocrine properties 1 2 . Unlike canonical FGFs, FGF21 has minimal heparin-binding affinity, allowing it to circulate freely in the bloodstream and function systemically rather than locally 1 .
Although detectable in various tissues including the pancreas, muscle, and adipose tissue, circulating FGF21 primarily originates from the liver 1 2 . FGF21 requires a receptor complex to signal, primarily consisting of FGFR1c (a cell surface receptor) and β-Klotho (KLB), a co-receptor protein 1 2 . This partnership is crucial—while FGFR1c is widely expressed across tissues, KLB shows restricted expression primarily in the liver, adipose tissue, and pancreas, conferring tissue specificity to FGF21 signaling 1 2 .
FGF21 first gained scientific attention for its remarkable ability to correct metabolic dysfunction and reduce body weight in models of type 2 diabetes and obesity 1 . Intervention studies in rodents and nonhuman primates demonstrated significant efficacy in improving multiple metabolic disorders, including weight reduction, improved insulin sensitivity, and correction of hyperglycemia and hyperlipidemia 1 2 .
The therapeutic potential of FGF21 in NASH lies in its unique ability to simultaneously target multiple pathological processes across different organ systems. Rather than focusing on a single pathway, FGF21 orchestrates a coordinated metabolic response throughout the body 5 .
Reduces lipotoxicity, decreases VLDL secretion, inhibits de novo lipogenesis, increases fatty acid oxidation
Increases insulin sensitivity, enhances glucose uptake, stimulates adiponectin, reduces lipolysis
Reduces sweet and alcohol consumption, addressing behavioral components of metabolic disease
Increases insulin sensitivity, oxidizes free fatty acids, reduces oxidative stress
| Target Organ/Tissue | Primary Receptor | Key Biological Actions | Therapeutic Benefit in NASH |
|---|---|---|---|
| Liver | FGFR2c + KLB | Reduces lipotoxicity, decreases VLDL secretion, inhibits de novo lipogenesis, increases fatty acid oxidation | Reduced liver fat, decreased oxidative stress, less inflammation and injury |
| Adipose Tissue | FGFR1c + KLB | Increases insulin sensitivity, enhances glucose uptake, stimulates adiponectin, reduces lipolysis | Improved systemic metabolism, reduced fatty acid influx to liver |
| Brain | FGFR1c + KLB | Reduces sweet and alcohol consumption | Addresses behavioral components of metabolic disease |
| Muscle | FGFR1c/FGFR3c + KLB | Increases insulin sensitivity, oxidizes free fatty acids | Reduced oxidative stress, improved glucose handling |
The compelling preclinical data on FGF21 has spurred the development of several long-acting analogs designed to overcome the limitations of native FGF21, which has a short half-life. These engineered variants show promising results in clinical trials, bringing this novel therapeutic approach closer to patients 5 .
This bivalent Fc-FGF21 analogue demonstrated impressive efficacy in the HARMONY trial, a phase 2b study involving patients with MASH and histologic stage F2 or F3 fibrosis. After 24 weeks of weekly subcutaneous injections, 39% and 41% of patients in the 28 mg and 50 mg dose groups, respectively, achieved at least one stage of fibrosis improvement without MASH worsening, compared to only 20% in the placebo group 5 . Notably, these effects intensified with longer treatment—at week 96, 46% and 75% of patients in the 28 mg and 50 mg dose groups, respectively, achieved this endpoint 5 .
This long-acting glycopegylated FGF21 analogue showed significant benefits in the phase 2b ENLIVEN trial. Treatment resulted in fibrosis improvement in 22%, 26%, and 27% of patients in the 15 mg, 30 mg, and 44 mg dose groups, respectively 5 . NASH resolution was achieved by 37%, 23%, and 26% of these groups, respectively 5 . Based on these promising results, pegozafermin is now advancing to phase 3 clinical trials.
This engineered FGF21 variant with extended half-life is administered monthly. In a phase 2a trial, 89% of patients receiving efimosfermin experienced at least a 30% reduction in hepatic fat fraction at week 12 5 . The drug demonstrated a favorable safety profile, with most treatment-emergent adverse events being mild to moderate gastrointestinal issues that resolved spontaneously 5 .
| Drug Candidate | Mechanism | Dosing Frequency | Fibrosis Improvement (%) | NASH Resolution (%) | Notable Metabolic Effects |
|---|---|---|---|---|---|
| Efruxifermin | Bivalent Fc-FGF21 analogue | Weekly | 39-41% (24 weeks) 46-75% (96 weeks) |
Data not specified | Significant improvement at higher doses with prolonged treatment |
| Pegozafermin | Glycopegylated FGF21 analogue | Weekly or every 2 weeks | 22-27% | 23-37% | Effective across different dosing regimens |
| Efimosfermin | Engineered FGF21 variant with long half-life | Monthly | Data not specified | Data not specified | 89% achieved ≥30% reduction in hepatic fat at 12 weeks |
Initial safety and dosing studies completed for all major FGF21 analogs
Proof of concept established with significant efficacy in fibrosis improvement and NASH resolution
Large-scale trials to confirm efficacy and monitor long-term safety
FDA and other regulatory agency review for market approval
The development of FGF21-based therapeutics represents a paradigm shift in NASH treatment, moving away from single-target approaches toward addressing the disease's multifaceted pathophysiology. The future of this field looks particularly promising in several directions:
First, combination therapies pairing FGF21 agonists with other agents like GLP-1 receptor agonists are under active investigation 5 6 . Early data suggests that adding efruxifermin to GLP-1 receptor agonist therapy significantly decreases hepatic fat fraction and improves noninvasive markers of fibrosis in patients with MASH and type 2 diabetes, with a tolerability profile comparable to either drug alone 5 .
Second, ongoing phase 3 clinical trials will further define the safety and efficacy of FGF21 analogs in patients with significant and advanced fibrosis, as well as those with cirrhosis 5 . These larger, longer-term studies will provide crucial information about the real-world potential of these therapies.
Third, researchers continue to work on better understanding the safety profile of FGF21 agonists, particularly regarding potential effects on bone mineral density—an important consideration for postmenopausal women who represent a significant proportion of the NASH population 5 .
Addresses multiple pathological processes simultaneously
Engineered analogs with extended half-life for convenient dosing
Potential for enhanced efficacy when combined with other therapies
The strategic targeting of FGF21 represents one of the most promising avenues in the battle against NASH. By harnessing and enhancing the body's natural metabolic regulatory systems, FGF21-based therapies offer the potential to address multiple facets of this complex disease simultaneously—from reducing liver fat and inflammation to improving systemic metabolic parameters and potentially reversing fibrosis.
While challenges remain in optimizing dosing, managing side effects, and potentially combining FGF21 agonists with other therapeutic approaches, the current clinical data provides substantial hope that this novel class of medications will soon provide relief for the millions of patients struggling with NASH and its devastating complications. The ongoing research into FGF21 biology and therapeutics truly represents the cutting edge of metabolic medicine, where understanding and manipulating our intrinsic physiological systems may yield transformative treatments for some of humanity's most pervasive health challenges.