FGF21
Fibroblast growth factor 21 (native hormone)
Written by Aaron CuhaReviewed Sep 2026
Also known as: Fibroblast growth factor 21
A liver hormone released by fasting, sugar and protein restriction that signals through beta-klotho. Engineered analogues improved liver fibrosis in phase 2b MASH trials of 222 and 128 people; lifespan extension exists only in transgenic mice.
Overview
FGF21 is an endocrine fibroblast growth factor made mainly by the liver in response to fasting, ketogenic states, protein restriction, sugar intake and PPAR-alpha activation. Unlike the paracrine FGFs it lacks the heparin-binding domain that keeps them local, so it circulates, and it can act only on tissues that express its obligate co-receptor beta-klotho, principally fat, liver and parts of the brain. Beta-klotho is a different gene and protein from alpha-klotho, the FGF23 co-receptor covered on the klotho page; the two are routinely confused.
Native FGF21 has not been developed as a drug, but the analogues have, and this page is the ligand hub for three of them on this site: efruxifermin, pegozafermin and efimosfermin. The randomised human evidence is in MASH (metabolic dysfunction-associated steatohepatitis) with liver biopsy endpoints. In ENLIVEN, funded by 89bio, 222 patients with biopsy-confirmed NASH and F2 or F3 fibrosis were randomised to pegozafermin 15 mg or 30 mg weekly, 44 mg every two weeks, or placebo for 24 weeks; fibrosis improved by at least one stage without NASH worsening in 7 percent on placebo, 22 percent on 15 mg, 26 percent on 30 mg and 27 percent on 44 mg, and NASH resolved in 2 percent versus 23 to 37 percent. In HARMONY, Akero's phase 2b of efruxifermin in 128 patients over 96 weeks, fibrosis improvement without MASH worsening was 19 percent on placebo, 30 percent on 28 mg and 49 percent on 50 mg (difference 31 percentage points, p 0.003). Nausea and diarrhoea were the most common adverse events with pegozafermin. Efruxifermin has three phase 3 trials enrolling 1,650, 2,150 and 700 people. No FGF21 analogue had a Drugs@FDA record on 11 September 2026.
The native hormone has one genuinely human finding. In 6,514 Danish participants a variant at the FGF21 locus was associated with higher candy consumption, and plasma FGF21 rose acutely after oral sucrose, framing FGF21 as a sugar-induced hormone that inhibits sweet and alcohol appetite. Exercise training also raises circulating FGF21 in trials of adults with overweight or obesity (13 trial arms, 280 people, pooled standardised mean difference 1.00).
The longevity claim is mouse only. Transgenic mice overexpressing FGF21 lived markedly longer, apparently by blunting growth hormone and IGF-1 signalling in the liver, and the same paper notes FGF21 blocks somatic growth and causes bone loss in mice. There is no human longevity or lifespan data of any kind, and bone loss is a recognised class concern for FGF21 pathway agonism whose human magnitude we did not verify from the trial reports.
Mechanism of action
Established in mice: fasting induces hepatic FGF21 through PPAR-alpha; FGF21 induces PGC-1alpha, drives fatty acid oxidation and ketogenesis, improves insulin sensitivity, suppresses growth hormone action, and causes bone loss. FGF21 signals through FGFR1c (and FGFR3c) only in the presence of beta-klotho, which is what restricts its action to fat, liver and specific brain regions. 2025 mouse work reports that FGF21 reverses MASH through coordinated CNS and liver actions and extends lifespan in diet-induced obesity independently of growth suppression. Established in humans: FGF21 rises acutely after sucrose ingestion and a common FGF21 variant associates with sweet and alcohol intake; exercise training raises circulating FGF21. Engineered analogues given weekly reduce liver fat, improve fibrosis histology and lower triglycerides in MASH, with nausea and diarrhoea as the main adverse effects. Whether those are systemic metabolic effects or liver-specific ones is the subject of a 2026 review.
Human evidence
The randomised human evidence is for engineered analogues, not native FGF21, and it is liver histology in MASH: phase 2b trials of pegozafermin (222 people, 24 weeks) and efruxifermin (128 people, 96 weeks) both improved fibrosis versus placebo. For the native hormone, human data are genetic and physiological: a locus variant tied to sweet intake, a sucrose-induced rise, and increases with exercise training.
- ENLIVEN (NEJM 2023): 222 randomised, pegozafermin, fibrosis improvement 22 to 27 percent versus 7 percent placebo at 24 weeks; NASH resolution 23 to 37 percent versus 2 percent. 89bio funded.
- HARMONY (Lancet 2025): 128 randomised, efruxifermin, fibrosis improvement 49 percent on 50 mg versus 19 percent placebo at 96 weeks (p 0.003); the 28 mg dose did not separate (p 0.19). Akero sponsored.
- Efruxifermin phase 3 programme: 1,650 (recruiting), 2,150 (recruiting) and 700 (active, not recruiting) participants across three trials.
- Inter99 cohort (Cell Metab 2017): 6,514 Danes, FGF21 rs838133 associated with candy intake; plasma FGF21 rose after oral sucrose.
- Exercise (Sports Med 2026 meta-analysis): 13 randomised trial arms, 280 adults with overweight or obesity, training raised circulating FGF21 (SMD 1.00, 95 percent CI 0.10 to 1.91).
- No human study has administered native FGF21, and no human study has tested any FGF21 pathway drug for weight loss as a primary endpoint, for ageing or for lifespan.
What this does not tell you: Analogue trials in people with biopsy-proven MASH say nothing about FGF21 in people without liver disease, and a histology endpoint at 24 to 96 weeks is not a clinical outcome; the phase 3 trials that could show one are years from completion. The analogues are engineered for long half-life and receptor properties that native FGF21 does not have, so their results are not results for the hormone. The mouse lifespan extension has no human counterpart of any kind. Bone loss is a recognised concern for FGF21 pathway agonism; we did not extract human bone density numbers from the trial reports and do not assert one. Both pivotal trials were manufacturer funded.
Reading the research record
FGF21 is the clearest example on this site of a native hormone whose evidence base belongs almost entirely to its analogues. Native FGF21 has a half-life too short to be a drug and no patent, so nobody has given it to people; the engineered versions (Fc-fused, glycopegylated, or otherwise stabilised) are each a company asset, and each company has paid for trials that measure what a liver drug needs to measure. That is why the human record is deep in MASH histology and empty everywhere else. Efruxifermin has already had a setback that its own page reports: the SYMMETRY phase 2b in compensated cirrhosis missed its primary endpoint at 36 weeks. Pegozafermin's programme moved to Roche in 2025. Efimosfermin, a monthly analogue, has its own page.
The longevity framing comes from a single line of mouse work. Transgenic overexpression extended lifespan in 2012, with a 2025 follow-up in obese mice, and the mechanism proposed, blunting of the growth hormone and IGF-1 axis, is the same one that connects FGF21 to reduced growth and bone loss in the same animals. Nothing in humans speaks to this either way. Any product framed as FGF21 for longevity is extrapolating from transgenic mice across a gap that the analogue trials, by design, cannot close.
The evidence, charted
Fig. 1 · evidence composition
4of 10 citations (40%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 7 distinct years, 2009 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2017
FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
In 6,514 participants of the Danish Inter99 cohort, FGF21 variant rs838133 was associated with higher candy consumption, with nominal associations to alcohol intake and smoking. In a separate clinical study plasma FGF21 rose acutely after oral sucrose and was higher in fasted sweet-disliking people.
Cell Metabolism - Human2023
Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH
ENLIVEN phase 2b, 222 randomised and 219 treated, biopsy-confirmed NASH with F2 or F3 fibrosis, 24 weeks. Fibrosis improvement without NASH worsening: 7 percent placebo, 22 percent on 15 mg weekly, 26 percent on 30 mg weekly (p 0.009), 27 percent on 44 mg every 2 weeks (p 0.008). NASH resolution: 2 percent placebo versus 37, 23 and 26 percent. Most common adverse events nausea and diarrhoea. Funded by 89bio.
New England Journal of Medicine - Human2025
Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial
128 randomised at 41 US centres, MASH with F2 or F3 fibrosis, efruxifermin 28 mg or 50 mg weekly or placebo. At 96 weeks, fibrosis improvement of at least one stage without MASH worsening: 19 percent placebo, 30 percent on 28 mg (difference 12 points, p 0.19), 49 percent on 50 mg (difference 31 points, 95 percent CI 12 to 49, p 0.003). Adverse events in 95 to 100 percent of every group including placebo. Sponsor Akero Therapeutics.
Lancet - Human2023
Efruxifermin phase 3 in non-cirrhotic MASH with fibrosis
Akero Therapeutics, phase 3, estimated enrolment 1,650, recruiting, primary completion estimated February 2033. Two further phase 3 trials: NCT06528314 in compensated MASH cirrhosis (2,150, recruiting) and NCT06161571 in non-invasively diagnosed MASH (700, active, not recruiting). Statuses checked 11 September 2026.
ClinicalTrials.gov - Review2026
The Use of FGF21 Analogues in MASH and MASH Cirrhosis: Metabolic Master Regulators or Liver-Specific Mechanisms?
Review asking whether the histological benefit of FGF21 analogues reflects systemic metabolic action or liver-specific mechanisms, a question that bears directly on whether anything on this page generalises beyond the liver.
JHEP Reports - Review2019
Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite
Review of the mouse, primate and human evidence that FGF21 signals from liver to brain to reduce sweet and alcohol preference.
Journal of Physiology - Animal2012
The starvation hormone, fibroblast growth factor-21, extends lifespan in mice
Transgenic overexpression of FGF21 markedly extended lifespan in mice without reducing food intake, apparently by blunting hepatic growth hormone and IGF-1 signalling. The same paper records that FGF21 blocks somatic growth and causes bone loss in mice. There is no human lifespan data.
eLife - Animal2025
FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression
In mice with diet-induced obesity, FGF21 extended lifespan through metabolic effects that did not depend on suppressing growth. Mouse only.
Cell Metabolism - Animal2009
FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response
In mice, FGF21 induced hepatic PGC-1alpha and coordinated the fasting response, including fatty acid oxidation, ketogenesis and gluconeogenesis. Foundational mouse mechanism.
Proceedings of the National Academy of Sciences - Animal2025
FGF21 reverses MASH through coordinated actions on the CNS and liver
In mice, FGF21's reversal of MASH required signalling in both the brain and the liver. Mouse mechanism for the human liver histology findings.
Cell Metabolism
Frequently asked questions
Does FGF21 extend lifespan?
In transgenic mice overexpressing it, yes, in a 2012 eLife paper and a 2025 follow-up in obese mice. There is no human lifespan, longevity or ageing data for FGF21 or any analogue. The same mouse work reports reduced growth and bone loss.
What has FGF21 done in human trials?
The trials are of analogues, not the hormone. Pegozafermin improved liver fibrosis in 22 to 27 percent of 222 MASH patients versus 7 percent on placebo at 24 weeks. Efruxifermin 50 mg improved fibrosis in 49 percent versus 19 percent on placebo at 96 weeks in 128 patients. Neither is approved; efruxifermin is in three phase 3 trials.
Is FGF21 the same thing as klotho?
No, but they are linked. FGF21 can only act on cells that express beta-klotho, its co-receptor. Beta-klotho is a different gene and protein from alpha-klotho, the kidney and brain protein covered on the klotho page, which is the co-receptor for FGF23 instead.
Does FGF21 reduce sugar cravings?
In mice and primates it reduces sweet consumption. In humans, a variant at the FGF21 gene was associated with eating more candy in 6,514 Danes, and plasma FGF21 rises after a sugar load. That is evidence FGF21 responds to sugar and may influence preference; no trial has given FGF21 or an analogue to people to test appetite.