Fibroblast growth factor receptor 4-Klotho beta receptor complex (FGFR4-KLB)

The Fibroblast growth factor receptor 4-Klotho beta (FGFR4-KLB) receptor complex is a specialized signaling unit primarily expressed in hepatocytes, where it serves as the high-affinity receptor for the hormone-like growth factor FGF19 (UniProt: P22607, Q86Z14). This complex plays a critical role in maintaining metabolic homeostasis by regulating bile acid synthesis through the suppression of the rate-limiting enzyme CYP7A1, as well as influencing glucose and lipid metabolism (PubMed: 15630444). In a physiological context, the binding of FGF19 to the FGFR4-KLB complex triggers the MAPK/ERK signaling pathway to modulate hepatic functions. Pathologically, aberrant activation of this signaling axis, often driven by FGF19 amplification or FGFR4/KLB overexpression, is a significant driver of hepatocellular carcinoma (HCC) and other liver-related malignancies (Lancet Oncol: 2019;20(10):1459-1469). Consequently, the complex has become a major therapeutic target, with selective FGFR4 inhibitors like fisogatinib and roblitinib being developed to treat FGF19-dependent cancers (PubMed: 28507065). Conversely, FGF19 analogs that activate the complex, such as aldafermin, are being investigated for the treatment of metabolic disorders like non-alcoholic steatohepatitis (NASH) (Lancet: 2018;391(10126):1174-1185).

Other names

FGFR4-beta-Klotho complexFGF19 receptor complexFGFR4-KLB complex

Selective inhibition of FGFR4 tyrosine kinase activity to block oncogenic signaling or agonism of the FGFR4-KLB complex via FGF19 analogs to suppress bile acid synthesis and improve metabolic parameters (PubMed: 28507065, Lancet: 2018;391(10126):1174-1185).