The emerging role of FGF21 in alcohol consumption and dependence: mechanisms and therapeutic prospects.

Alcohol use disorder (AUD) is a neuropsychiatric recurring, persistent illness, characterized by the consumption of alcohol, irrespective of its physical, psychological, and social effects. The clinical manifestations are cravings, anxiety, mood disorders, mental defects, and liver dysfunction, and this may increase the risk of morbidity and mortality in AUD. Fibroblast growth factor 21 (FGF21), an endocrine protein, is mainly synthesized in the liver. It is an important metabolic homeostatic hormone that controls the metabolism of glucose and lipids. There is also growing evidence that the FGF21 signal is relayed to the brain via the fibroblast growth factor receptor 1c (FGFR1c)-β-klotho (KLB) receptor complex to prevent the consumption of alcohol. It is a mechanical controller of the mesolimbic dopamine, and a neuroendocrine controller of the metabolic stress, which ultimately leads to the loss of alcohol craving and intake, and which in turn reduces the alcohol damage to the liver. Pharmacological and genetic preclinical findings have revealed that exogenous FGF21 or long-acting FGF21 analogues inhibit alcohol preference, highlighting it as a promising biomarker and therapeutic target, although current clinical evidence remains limited. The paper aims to critically synthesise available literature to identify the biological role of FGF21 in AUD and its potential therapeutic uses, along with highlighting important gaps and future research directions to improve FGF21-based interventions in the treatment of AUD.