The role of β-Klotho in FGF signaling: from molecular insights to therapeutic innovations.

β-Klotho (KLB) is a transmembrane protein expressed in the liver, pancreas, hypothalamus, and adipose tissue, where it acts as an essential coreceptor for fibroblast growth factor 19 and 21 (FGF19 and FGF21). By facilitating their binding to fibroblast growth factor receptors (FGFRs), KLB helps form critical endocrine axes that regulate a wide range of physiological processes and are implicated in various diseases. This review summarizes current knowledge of KLB, focusing on its structural and functional features as well as the physiological roles of the FGF19-KLB and FGF21-KLB axes. A comprehensive analysis of the literature confirms that KLB is indispensable for high-affinity signaling of FGF19 and FGF21. The FGF19-KLB axis primarily controls bile acid synthesis, glucose metabolism, and energy expenditure, thereby modulating glucose/lipid homeostasis, energy balance, and insulin sensitivity. Dysregulation of these axes is linked not only to metabolic disorders such as diabetes, metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and obesity but also to certain malignancies and neurological disturbances, underscoring their broad role in disease. Growing evidence highlights the therapeutic potential of targeting these pathways, supporting their value as drug targets for novel treatments, especially in metabolic disease. This review consolidates understanding of the central roles played by KLB-mediated signaling in metabolic homeostasis and disease, examines its emerging relevance in cancer and neural regulation, and emphasizes the need to advance KLB biology to fully exploit its potential as a multifunctional therapeutic target.