FIBROBLAST growth factor 21 (FGF21) signalling reduced problematic alcohol use and alcohol-related liver disease (ARLD) risk in a large human genetic analysis, strengthening the case for repurposing FGF21 analogues in addiction medicine.
Problematic alcohol use and alcohol use disorder (AUD) remain major contributors to global morbidity and mortality, with ARLD a leading cause of preventable liver failure. Although treatment options for AUD are limited, analogues of FGF21, a liver-derived hormone, are currently in development for metabolic dysfunction-associated steatotic liver disease (MASLD). Until now, their potential impact on alcohol behaviours and ARLD risk had been unclear.
Using genome-wide association data from UK Biobank, FinnGen, the Million Veterans Program, and GenomALC, researchers applied Mendelian randomisation to evaluate whether genetically predicted increases in circulating FGF21 influenced problematic alcohol use, binge drinking, weekly alcohol intake, and ARLD.
FGF21 Signalling Reduced Problematic Alcohol Use and Alcohol-Related Liver Disease
Genetically higher FGF21 levels were associated with lower problematic alcohol use (beta: -0.097; 95% CI: -0.135–-0.059; p=6.13×10⁻⁷), fewer binge episodes, reduced weekly alcohol intake, and lower ARLD risk (odds ratio: 0.79; 95% CI: 0.638–0.987; p=0.038).
Multivariable Mendelian randomisation demonstrated that these protective effects were mediated by behavioural pathways, including reduced alcohol consumption and improved dietary patterns, as well as increased basal metabolic rate. In comparative analyses of MASLD-related genes, only FGF21 showed consistent protective effects across alcohol behaviours and ARLD risk; other targets such as PNPLA3 and HSD17B13 did not demonstrate similar benefits.
Receptor-focused analyses highlighted brain-region specificity. Hippocampal expression of fibroblast growth factor receptor 3 (FGFR3) and basal ganglia expression of β-Klotho were associated with reduced ARLD risk, supporting a biologically plausible liver–brain axis through which FGF21 signalling may influence alcohol intake.
Safety Profile and Clinical Implications of FGF21 Signalling
A phenome-wide Mendelian randomisation analysis across 1,022 traits identified 28 Bonferroni-significant protective associations with higher genetically predicted FGF21, including reduced gout risk. Importantly, hepatic FGF21 expression showed fewer potential on-target liabilities than PNPLA3 or HSD17B13.
Although the analysis was restricted to individuals of European ancestry and relied on Mendelian randomisation assumptions, the findings provided robust human genetic evidence that FGF21 signalling mitigated hazardous drinking and ARLD risk via behavioural and metabolic pathways.
These results suggested that FGF21 analogues, already in clinical development for MASLD, may offer a precision-medicine strategy for AUD and ARLD. Future clinical trials will be needed to determine whether pharmacologically enhancing FGF21 signalling can translate these genetic findings into effective therapies.
Reference
Rosoff DB et al. Genetic evidence that FGF21 signaling reduces problematic alcohol use and alcohol‐related liver disease. J Hepatol. 2026; DOI:10.1016/j.jhep.2026.01.025.
Featured image: Brian Jackson on Adobe Stock
