Li Xiaokun, Lu Weiqin, Kharitonenkov Alexei, Luo Yongde
School of Pharmacological Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA.
J Intern Med. 2024 Mar;295(3):292-312. doi: 10.1111/joim.13767. Epub 2024 Jan 11.
Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.
人成纤维细胞生长因子19（FGF19，在啮齿动物中为FGF15）通过负反馈机制在控制胆汁酸（BA）合成中起核心作用。这一过程涉及餐后BA激活的回肠法尼醇X受体与与成纤维细胞生长因子受体4（FGFR4）激酶复合的肝脏β-klotho（KLB）共受体之间的相互作用。此外，FGF19通过协调外周功能性KLB和FGFR1-3受体复合物的反应来调节葡萄糖、脂质和能量代谢。在药理学上，天然FGF19或其类似物可降低升高的BA水平、脂肪含量和侧支组织损伤。这使得它们在治疗胆汁淤积性疾病如原发性胆汁性或硬化性胆管炎（PBC或PSC）和代谢异常如非酒精性脂肪性肝炎（NASH）方面有效。然而，长期给予FGF19会通过激活FGFR4依赖性有丝分裂或肝脏再生途径在小鼠中驱动肿瘤发生，这在人类中可能是一个问题。阻断FGF19或FGFR4信号的药物在动物模型中已显示出在预防FGF19反应性肝细胞癌（HCC）发展方面的强大效力。最近的1/2期临床试验已证明几种基于FGF19的药物在选择性治疗PBC、PSC、NASH或HCC患者方面有令人鼓舞的结果。本综述旨在提供针对胆汁淤积性、代谢性和癌症疾病患者的靶向FGF19-FGFR4信号通路的类似物和拮抗剂临床开发的最新情况。我们还将分析潜在的安全性和机制问题，这些问题应指导未来的研究和高级试验。
