Keywords: FGFR4, Fibroblast Growth Factor Receptor 4, FGF19, FGF4, Hepatocellular Carcinoma, Alcoholic Liver Disease, FGFR4 Inhibitors, BB102, Irpagratinib

FGFR4, the fourth member of the fibroblast growth factor receptor family, was long considered a "peripheral player" in this group. It wasn't until the critical pathogenic role of the FGF19-FGFR4 signaling axis in hepatocellular carcinoma (HCC) was gradually revealed that FGFR4 truly moved from the sidelines to center stage. Between 2025 and 2026, the FGFR4 target field witnessed密集 breakthroughs: the FGFR4 inhibitor irpagratinib (ABSK-011)先后 received FDA Fast Track designation (February 2026) and EMA orphan drug designation (April 2026), while the domestic BB102 project initiated Phase II clinical trials at Beijing Chaoyang Hospital, and HH-009 injection entered Ib/II phase registration clinical trials. Concurrently, FGF4, another important ligand of FGFR4, was systematically elucidated for its role in alcoholic liver disease (ALD) and bile acid metabolism regulation. Beyond the HCC领域, FGFR4 was recently identified as a key regulatory target in colorectal cancer stem cells (CRC CSCs). This article will systematically梳理 the molecular signaling basis of FGFR4, its dual roles in肿瘤 and metabolic diseases, and the latest clinical translation进展 in targeted therapies.

FGFR4 is a member of the receptor tyrosine kinase family, alongside FGFR1, FGFR2, and FGFR3. Although these four receptors share high homology in their extracellular domains, FGFR4 exhibits unique characteristics in ligand selectivity, tissue distribution, and signal output.

The FGFR4 protein consists of an N-terminal signal peptide, three immunoglobulin-like domains (IgI, IgII, IgIII), an acidic amino acid-rich acid box region, a transmembrane domain, and an intracellular split tyrosine kinase domain. The IgIII domains of FGFR1-FGFR3 can generate two splice variants, b and c, through alternative splicing, thereby modulating affinity for different FGF ligands. In contrast, the IgIII domain of FGFR4 lacks such splice variants, resulting in more limited ligand selectivity, primarily recognizing specific ligands like FGF19 and FGF4.

The core of FGFR4 signal transduction lies in ligand-induced receptor dimerization and trans-phosphorylation. Taking FGF19 as an example, this ligand requires协同 action with the co-receptor β-Klotho to effectively activate FGFR4. Upon ligand binding, FGFR4 undergoes homodimerization, and multiple tyrosine residues in the intracellular kinase domain are phosphorylated, subsequently activating downstream RAS-MAPK and PI3K-AKT signaling pathways via the adaptor protein FRS2, ultimately driving a series of biological effects such as cell proliferation, survival, and migration. In HCC, FGF19 overexpression leads to sustained activation of FGFR4 signaling, becoming a central环节 in tumor progression.

2.1 Target Logic and Unmet Clinical Needs
Liver cancer is the third leading cause of cancer-related deaths globally, with HCC accounting for 75%-85%. Approximately 30% of HCC patients worldwide exhibit FGF19 overexpression, a subtype associated with more aggressive disease behavior and poorer prognosis. However, first-line immune checkpoint inhibitors combined with anti-angiogenic therapy offer limited benefits in this patient population, and there are no approved therapies targeting the FGFR4/FGF19 pathway, representing a significant unmet clinical need.

FGFR4 is highly expressed in HCC tissues, and its expression levels are closely correlated with patient overall survival rates, further establishing FGFR4 as an excellent therapeutic target for HCC.

2.2 Clinical Breakthroughs in Small-Molecule FGFR4 Inhibitors
Irpagratinib (ABSK-011) is a highly selective oral small-molecule FGFR4 inhibitor independently developed by Abbisko Therapeutics. Data presented at the 2025 ESMO GI Congress showed that irpagratinib combined with atezolizumab (Tecentriq) achieved an objective response rate exceeding 50% in FGF19-overexpressing HCC patients, regardless of whether they were treatment-naïve or immunotherapy-experienced, with a median progression-free survival of over 7 months and no new safety signals. In refractory FGF19-positive HCC patients previously treated with immune checkpoint inhibitors and multi-target TKIs, irpagratinib monotherapy at 220 mg twice daily achieved an ORR of 44.8%, a disease control rate of 79.3%, a median duration of response of 7.4 months, and a median PFS of 5.5 months. Based on these data, irpagratinib received breakthrough therapy designation from China's NMPA in 2025, FDA Fast Track designation in February 2026, and EMA orphan drug designation in April 2026, intended for use in advanced HCC with FGF19 overexpression.

BB102 is another oral FGFR4 inhibitor developed by Beijing Bohui Biotechnology. In May 2026, Phase II clinical trials for the BB102 project were officially initiated at Beijing Chaoyang Hospital, targeting advanced or unresectable FGF19-overexpressing liver cancer. Notably, the FGFR4 target was ranked first in the 2025 CSCO Liver Cancer Annual Focus on Clinical Targets, and BB102 has already demonstrated良好的 safety and significant therapeutic efficacy in Phase I trials. Currently, drugs targeting this pathway globally are all in Phase II clinical stages.

Additionally, HH-009 (developed by Huahui Anjian) is a fully humanized IgG4 monoclonal antibody targeting the N-terminus of FGF19. It competitively blocks the interaction between FGF19 and the FGFR4 receptor, inhibiting downstream proliferative signaling pathways while improving the immunosuppressive microenvironment and tumor cachexia. In April 2026, the Ib/II phase registration clinical trial for HH-009 injection was率先 launched at Nanjing Tianyinshan Hospital, with Professor Qin Shukui and Academician Fan Jia serving as Co-Leading PIs. In the Phase Ia study of this drug, the median overall survival in the FGF19-positive HCC subgroup reached 17 months, and higher FGF19 expression levels may correlate with better efficacy.

Unlike FGF19, which functions as an endocrine ligand, FGF4 belongs to the paracrine FGF family and primarily acts locally in the liver. In February 2025, a study published in Hepatology by the team of Academician Li Xiaokun from Wenzhou Medical University, led by Song Lintao and Huang Zhifeng,首次 systematically elucidated the molecular mechanism by which FGF4 exerts hepatoprotective effects via the FGFR4-ERRγ-CYP2E1 signaling axis. Alcoholic liver disease (ALD) affects over 350 million patients worldwide, yet clinical treatment remains limited to abstinence interventions and a handful of symptomatic drugs. This study found that FGF4 mRNA and protein levels were significantly upregulated in the liver tissues of ALD patients, positively correlating with disease severity. After hepatocyte-specific knockout of Fgf4, alcohol-induced hepatic oxidative stress, inflammatory responses, apoptosis, and liver injury were markedly exacerbated. Mechanistic studies revealed that FGF4 activates FGFR4, phosphorylates ERRγ to promote its ubiquitination and degradation, thereby inhibiting CYP2E1 transcriptional activity and reducing the toxic damage caused by ethanol metabolites.

Additionally, a study published in Cell Metabolism in October 2025 discovered that hepatic FXR-FGF4 maintains bile acid homeostasis under cholestatic stress through the FGFR4-LRH-1 signaling node. This finding揭示了 the complementary role of the FGF4-FGFR4 axis in bile acid homeostasis regulation, independent of the classical intestinal FGF19 signaling pathway.

FGFR4's oncogenic functions are not limited to hepatocellular carcinoma. A study published in Cancers in January 2026首次 identified FGFR4 as a key regulatory target in colorectal cancer stem cells (CSCs). The study found that FGFR4 is highly expressed in colorectal CSCs, regulating their proliferation, migration, and tumorigenic capabilities. The research team developed the first anti-FGFR4 monoclonal antibody, 3B6, which demonstrated potent anti-tumor activity both in vitro and in patient-derived xenograft models, offering a new therapeutic direction for metastatic colorectal cancer.

In other肿瘤 fields, a study published in Frontiers in November 2025 revealed the mechanism by which FGF17 drives non-small cell lung cancer progression via the FGFR4/MEK5/ERK5/NRF2 signaling axis. FGF17 is activated under conditions of GLUL overexpression, stimulating FGFR4 signaling to maintain redox homeostasis and promote epithelial-mesenchymal transition, thereby accelerating tumor invasion and migration. This discovery expands the potential value of FGFR4 as a therapeutic target in respiratory system tumors.

Although FGFR4 inhibitors have demonstrated anti-tumor activity in clinical settings, drug resistance remains an unavoidable challenge. Studies have found that reactivation of the PI3K/mTOR signaling pathway is one of the key mechanisms underlying acquired resistance to the FGFR4 inhibitor FGF401. This issue suggests that the long-term efficacy of FGFR4 inhibitors may require combination therapies targeting downstream pathways.

In addressing drug resistance, a study published in the Journal of Experimental & Clinical Cancer Research in March 2026 presented an innovative approach: the marine natural product Psammaplysene D directly targets FGFR4, downregulates CYP26A1 expression, and elevates retinoic acid levels, thereby inducing ferroptosis in sorafenib-resistant liver cancer models and reversing resistance. The study also found that FGFR4 is highly expressed in the liver, and its abnormal activation is closely related to liver cancer resistance, providing a new strategy for overcoming resistance in FGFR4-targeted therapies.

In terms of novel molecular types, a team from Zhejiang Sci-Tech University developed the high-affinity FGFR4-specific aptamer FGFR4zxh-11bm, which effectively blocks FGF19-FGFR4 interaction, inhibits downstream FRS2 phosphorylation, and suppresses HCC cell migration, offering a nucleic acid drug alternative to antibodies and small molecules for FGFR4-targeted therapy. Additionally, FGFR4-ADCs (e.g., 3A11-MMAE) are being explored for indications such as breast cancer and rhabdomyosarcoma.

FGFR4 has evolved from a basic metabolic biology concept to a差异化 and highly translatable target spanning肿瘤, liver diseases, metabolic disorders, and other fields. Current core strategic directions in the field include:

In terms of indication布局, FGF19-positive HCC represents the most mature target population globally, accounting for approximately 30% of all HCC cases. Multiple FGFR4 inhibitors have entered Phase II or later clinical stages, with industry focus shifting from monotherapy exploration to a first-line treatment paradigm centered on combination immunotherapy. In drug resistance management, elucidation of resistance mechanisms such as PI3K/mTOR reactivation is driving early-stage development of next-generation inhibitors and combination strategies. In technological paradigm迭代, diverse molecular types—including antibodies (e.g., 3B6), aptamers (e.g., FGFR4zxh-11bm), and ADCs (e.g., 3A11-MMAE)—are expanding the druggable boundaries of the FGFR4 target from various angles. Industry attention is shifting from单纯 small-molecule covalent inhibition to diverse molecular types and conditional activation modalities.

It is anticipated that FGFR4-targeted drugs will率先 gain approval for FGF19-positive HCC, a global unmet medical need, while applications of FGFR4 in other肿瘤 and metabolic diseases will continue to expand the clinical boundaries of this target.