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This process involves a postprandial crosstalk between the BA\u2010activated 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\u20103 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\u2010dependent 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\u2010responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1\/2 clinical trials have demonstrated promising results for several FGF19\u2010based 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\u2013FGFR4 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.<\/jats:p>","DOI":"10.1111\/joim.13767","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:53:05Z","timestamp":1705020785000},"page":"292-312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Targeting the FGF19\u2013FGFR4 pathway for cholestatic, metabolic, and cancerous diseases"],"prefix":"10.1111","volume":"295","author":[{"given":"Xiaokun","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacological Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences School of Pharmacy University of Texas at El Paso  El Paso Texas 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