{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have demonstrated that fibroblast growth factor receptor‐4 (FGFR4) plays a multifaceted oncogenic role across a wide spectrum of human malignancies. Activating mutations—including missense changes such as Y367C and the prevalent Gly388Arg polymorphism—enhance receptor stability and prolong downstream signaling through effectors such as STAT3, MAPK, β‐catenin and Src. This sustained signaling has been implicated in increased cell proliferation, epithelial–mesenchymal transition, invasion and metastasis in diverse tumors including rhabdomyosarcoma, breast, prostate, thyroid, melanoma, colorectal, hepatocellular and ovarian carcinomas. In many of these cancers, an autocrine loop driven by ligands such as FGF19 further potentiates FGFR4 activity, underscoring its role as a critical mediator of tumor progression and aggressive disease behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFGFR4‐driven signaling also contributes to therapeutic resistance. In several tumor models, aberrant FGFR4 activation has been linked to reduced sensitivity to standard chemotherapeutic agents, hormonal therapies (including tamoxifen) and targeted treatments such as anti‐HER2 antibodies and multi‐kinase inhibitors (e.g. sorafenib). Preclinical investigations using structure‐based drug design, covalent kinase inhibitors and blocking antibodies that disrupt FGF19–FGFR4 interactions have shown that inhibition of this receptor can re‐sensitize resistant tumor cells by diminishing pro‐survival pathways and promoting apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "41"}, {"type": "fg_f", "ref": "33"}, {"type": "fg_f", "ref": "36"}, {"type": "fg_f", "ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its oncogenic functions, FGFR4 plays a pivotal role in metabolic homeostasis. In the liver, FGFR4 is the predominant FGFR isoform mediating the endocrine actions of FGF19—distinct from FGF21—and regulates bile acid synthesis by repressing cholesterol 7α‐hydroxylase (CYP7A1) via PI3K and JNK‐dependent pathways. Unique intracellular trafficking characteristics of FGFR4—including reduced ubiquitylation and predominant recycling rather than lysosomal degradation—further distinguish its signaling profile from that of other FGFR family members, thereby extending the duration of its metabolic and proliferative outputs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "42"}, {"type": "fg_f", "ref": "21"}, {"type": "fg_f", "ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Johannes Bange, Dieter Prechtl, Yuri Cheburkin, et al. 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