FGF19/15 is primarily synthesized and secreted by ileal intestinal epithelial cells^[17]. Its expression is precisely regulated by the bile acid-FXR pathway; postprandial elevation of intestinal bile acid levels activates FXR in the ileum, thereby inducing the transcription of the FGF19/15 genes and protein secretion^[11,19]. The liver is the most critical target organ for FGF19/15. Through systemic circulation, FGF19/15 acts on the liver to regulate various metabolic processes, including gluconeogenesis, bile acid synthesis, and glycogen and protein synthesis, independently maintaining hepatic metabolic homeostasis during the late postprandial phase, when insulin levels decline^[20]. In human-oriented contexts, these effects are generally described as FGF19-mediated responses, whereas in mouse models they are usually attributed to FGF15. This distinction is important because many metabolic and tissue-repair conclusions are derived from murine Fgf15-deficient or Fgf15-overexpression models but are extrapolated to human FGF19 biology^[11].

Experimental studies indicate that FGF19/15 contributes to adipose-tissue plasticity and thermogenic adaptation^[13]. Central FGF19 signaling can also enhance energy expenditure and adipose thermogenesis through sympathetic activation^[21].

FGFR4 is the key receptor for FGF19/15 signaling in the liver^[11]. By binding to FGFR4, FGF19/15 activates the downstream fibroblast growth factor receptor substrate 2 alpha (FRS2α)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, thereby suppressing the activity of cAMP response element-binding protein (CREB) and downregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. In FGFR4-knockout mice, the expression of hepatic gluconeogenic genes such as Pgc1a, G6pase, and Pepck is significantly elevated, and postprandial glucose clearance is impaired^[20]. Notably, inhibition of hepatic lipogenesis by FGF19/15 relies on the small heterodimer partner (SHP) rather than directly through the downstream pathway of FGFR4, indicating that FGFR4 is a major receptor component for hepatic FGF19/15 signaling, whereas some metabolic outputs are further shaped by SHP-dependent regulatory mechanisms^[17].

KLB is an essential coreceptor for FGF19/15 signaling^[22]. In the liver, FGFR4-KLB is the predominant receptor complex, whereas alternative FGFR/KLB complexes may contribute to metabolic responses in extrahepatic tissues^[11,23]. Liver-specific KLB deletion renders FGF19 unable to suppress hepatic gluconeogenesis, indicating that KLB is a critical determinant of tissue-specific functionality of FGF19/15^[11]. Under pathological conditions such as obesity, hepatic microRNA-34a is abnormally elevated in mice and targets and suppresses KLB expression, leading to reduced hepatic responsiveness to FGF19 and exacerbating hepatic lipid accumulation^[24]. Under physiological conditions, FXR transiently induces hepatic KLB expression, thereby priming the liver for FGF19/15 signal transduction, as illustrated in Figure 1.

The chimeric protein Fibapo, derived from FGF19, significantly enhanced hepatocyte proliferation (Ki-67+), accelerated liver mass recovery, and improved survival rates in acute liver injury models such as acetaminophen toxicity and aged mice undergoing partial hepatectomy. This is achieved by activating the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal S6 kinase (p70S6K) pathway, upregulating cell cycle genes such as Foxm1b and Cdc25b, and downregulating hepatocyte nuclear factor α^[25,26]. For liver protection, activation of the intestinal FXR-FGF19/15 axis by C. scindens suppresses hepatic CYP7A1 expression and reduces bile acid synthesis, alleviating cholestatic liver injury and fibrosis^[11].

FGF19/15 is a key hormone involved in the negative feedback regulation of bile acid synthesis^[27]. Postprandial elevation of bile acid levels in the ileum activates FXR, inducing FGF19/15 expression and secretion into the bloodstream. FGF19/15 then binds to the FGFR4/KLB receptor complex on hepatocytes, suppressing the expression of CYP7A1 and thereby reducing bile acid synthesis^[11,28,29]. In Fgf15-knockout mice, Cyp7a1 expression was significantly upregulated and the bile acid pool expanded, further confirming its central role in maintaining bile acid homeostasis^[30]. In addition to bile acid regulation, FGF19 also exhibits insulin-independent glucose-lowering effects. It inhibits hepatic gluconeogenesis by downregulating key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, thereby reducing endogenous glucose production^[20]. FGF19 also promotes hepatic protein and glycogen synthesis; in insulin-deficient diabetic animal models, FGF19 treatment restores depleted hepatic glycogen through an insulin-independent postprandial pathway^[31]. Clinical observations have revealed that plasma FGF19 levels are reduced in patients with type 2 diabetes but significantly increase after bariatric surgery, further supporting its role in glucose homeostasis^[32]. Experimental evidence further suggests that intestinal FGF15 signaling interacts with bile acid metabolism and energy expenditure during metabolic surgery, although its contribution to the metabolic benefits of surgery is context-dependent^[33].

Although FGF19/15-mediated enterohepatic signaling is primarily recognized as an endocrine pathway controlling bile acid synthesis and hepatic metabolic homeostasis, metabolic liver diseases such as MASLD are also shaped by persistent immune activation and inflammatory remodeling^[34,35]. Therefore, the biological effects of FGF19/15 signaling should be considered within a broader immunometabolic framework involving endocrine regulation, immune-cell communication, and tissue-specific inflammatory responses.

The spleen-liver axis represents an additional regulatory layer that contributes to hepatic inflammation and fibrosis progression^[36]. In metabolic disorders, splenic immune remodeling may alter the distribution and activation state of several immune populations, including splenic monocytes, myeloid-derived suppressor cells (MDSCs), and natural killer T (NKT) cells^[36]. These immune subsets can influence hepatic inflammatory responses through migration toward the liver and/or secretion of soluble mediators. Previous studies have implicated cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β) in promoting Kupffer cell activation, hepatic stellate cell (HSC) stimulation, and fibrogenic remodeling^[37].

From a mechanistic perspective, FGF19/15 signaling and the spleen-liver axis may converge on shared pathological processes during MASLD progression. Under physiological conditions, FXR activation induces intestinal FGF19/15 secretion, which subsequently acts through hepatic FGFR4/KLB signaling to suppress CYP7A1-mediated bile acid synthesis and maintain metabolic homeostasis. However, chronic metabolic stress and inflammatory activation may enhance splenic immune responses and increase hepatic inflammatory burden through immune-cell trafficking, cytokine release, and portal circulation-mediated communication. The spleen-liver axis has been proposed to involve bidirectional interactions mediated by immune-cell movement and inflammatory signaling, including splenic monocytes, natural killer (NK)/NKT cells, TNF-α, IL-6, and TGF-β-related pathways^[36].

Importantly, current evidence does not establish a direct molecular pathway whereby FGF19/15 specifically regulates splenic immune-cell recruitment or activation. Instead, these two systems should be considered as interacting but distinct regulatory networks: FGF19/15 functions primarily as an endocrine metabolic coordinator, whereas the spleen-liver axis provides an immunological and inflammatory regulatory layer. Understanding the interaction between these pathways may help explain the heterogeneous therapeutic responses observed with FGF19-based interventions and may provide additional considerations for patient stratification according to metabolic and inflammatory states^[38].

FGF19 acts on the hypothalamus to integrate peripheral and environmental signals and regulate energy metabolism. Central FGF19 signaling enhances sympathetic nervous system activity and stimulates adipose-tissue thermogenesis^[21]. FGF19 can also activate thermogenic adipose programs, although its anti-obesity effects do not strictly require uncoupling protein 1 (UCP1)-dependent thermogenesis^[39]. Transgenic mice expressing human FGF19 display increased metabolic rate, decreased adiposity, and resistance to diet-induced obesity, supporting a systemic role in energy expenditure^[40]. In addition, FGF19 mitigates peripheral inflammation and enhances cold tolerance. Cold exposure increases hypothalamic FGF19 receptor expression, suggesting an adaptive role of FGF19 in energy balance and thermoregulation. These benefits disappear when sympathetic nervous system activity is inhibited, further confirming its dependence on sympathetic activation^[21].

FGF19 and its murine ortholog FGF15 exhibit a striking dual role in tumorigenesis and progression, and their functions are highly dependent on tissue context and molecular background. In hepatocellular carcinoma (HCC), FGF19/15 exerts a clear pro-tumorigenic effect via the FGF19-FGFR4-KLB signaling pathway^[41-43]. Clinical samples show co-upregulation of pathway members in nonalcoholic steatohepatitis (NASH; now termed MASH)-related HCC, and animal models have confirmed that elevated FGF15 expression promotes HCC development^[44]. Mechanisms include activation of epithelial-mesenchymal transition and the Wnt/β-catenin pathway, enhancing migration, invasion, and proliferation, which are reversible by pathway inhibitors. FGF19/15 also upregulates stem cell markers and synergizes with autocrine/paracrine signaling and lipid metabolism crosstalk to promote cancer^[44].

Conversely, in FGFR4-deficient breast cancer models, ileal FGF15 expression is markedly upregulated, accompanied by systemic increases in FGF21 and adiponectin and broader metabolic remodeling associated with delayed tumor progression and improved survival^[23]. The associated metabolic remodeling may involve FGF15 and FGF21 signaling through FGFR1-KLB; however, because FGF15, FGF21, and adiponectin changed concurrently in this model, the specific contribution of FGF15 cannot be isolated^[23]. Thus, this model does not establish a direct tumor-suppressive effect of FGF19/15, but it illustrates how systemic endocrine and metabolic context can modify tumor progression. Major physiological functions and the pro-tumorigenic HCC context are summarized in Figure 2.

Sex-related biological factors may influence FGF19/15 signaling through modulation of bile acid metabolism, nuclear receptor activity, and hepatic responsiveness^[46]. Estrogen signaling affects hepatic lipid metabolism, inflammatory responses, and bile acid composition, all of which are closely connected with the FXR-FGF19/15 pathway^[47,48].

Because intestinal FXR activation is a primary regulator of FGF19/15 production, sex-dependent differences in bile acid profiles and FXR activity may contribute to variation in FGF19/15 secretion between males and females^[49,50]. In addition, differences in hepatic expression or activity of FGFR4 and KLB may alter tissue sensitivity to circulating FGF19^[51].

Recent evidence has begun to link FGF15 signaling with hepatic sexual dimorphism; however, direct evidence demonstrating sex-specific regulation of the FGF19/15-FGFR4/KLB axis remains limited. Future studies using sex-stratified experimental designs are required to determine whether sex hormones directly modify FGF19/15 signaling activity^[52].

The FGF19/15 axis plays an important role in metabolic regulation by controlling hepatic glucose production, lipid metabolism, and energy homeostasis^[18,53,54]. However, metabolic disorders display substantial sex-dependent differences in prevalence, progression, and therapeutic responses, suggesting that the biological effects of FGF19/15 signaling may be modified by sex-specific factors^[55,56].

In glucose metabolism, FGF19 improves metabolic control through insulin-independent mechanisms and regulates hepatic glucose utilization^[57]. Differences in insulin sensitivity, adipose tissue distribution, and hormonal status between males and females may influence the metabolic consequences of altered FGF19 signaling.

Similarly, FGF19/15 regulates lipid homeostasis through bile acid metabolism and hepatic lipid handling^[22,58]. The hepatic KLB-dependent response to FGF19 is essential for maintaining lipid balance, and disruption of this pathway leads to metabolic abnormalities^[59]. Whether sex-dependent differences in KLB expression or bile acid composition contribute to differential responses remains an important area of investigation.

These observations suggest that biological sex should be considered when evaluating FGF19-based metabolic therapies.

Sex differences are particularly evident in metabolic-associated liver diseases, including MASLD and MASH^[60-62]. Before menopause, estrogen signaling provides protective effects against hepatic lipid accumulation, inflammation, and fibrosis development, whereas estrogen decline after menopause increases metabolic vulnerability^[63].

Because FGF19/15 regulates bile acid synthesis, hepatic lipid metabolism, and tissue repair, alterations in this pathway may contribute to sex-dependent susceptibility to liver diseases. Reduced FGF19 activity or impaired hepatic responsiveness to FGF19 signaling has been associated with metabolic dysfunction and abnormal hepatic lipid accumulation.

Sex differences are also observed in cholestatic liver diseases. Several cholestatic disorders exhibit sex-biased prevalence patterns, suggesting potential interactions between sex hormones and bile acid regulatory pathways^[64-66]. Through regulation of CYP7A1 suppression and hepatocyte proliferation, FGF19/15 signaling may participate in sex-dependent responses to hepatic injury and regeneration.

Nevertheless, direct evidence linking sex differences with FGF19/15-mediated liver repair remains limited and requires further investigation.

Aberrant activation of the FGF19-FGFR4/KLB signaling pathway contributes to tumor development, particularly in HCC^[67]. However, cancer susceptibility and progression are strongly influenced by biological sex through differences in hormone signaling, immune regulation, and metabolic environments^[68,69].

Androgen and estrogen signaling can modify hepatic tumor development and may interact with metabolic pathways involved in FGF19/FGFR4 activation^[70]. Therefore, sex-dependent regulation of FGF19 signaling may contribute to differences in tumor biology and therapeutic responses.

Understanding whether sex-specific factors influence FGF19-driven tumor progression may provide valuable information for biomarker development and personalized therapeutic strategies targeting FGFR4 or related pathways^[71].

FGF19/15 expression in the ileum is tightly regulated by the transcription factors FXR and T-cell factor 4 (TCF4). FXR, the central regulator of bile acid homeostasis, binds directly to regulatory elements controlling FGF19/15 transcription after activation by intestinal bile acids^[11]. TCF4 also directly regulates Fgf15 and cooperates with the intestinal bile-acid signaling program to maintain bile acid and lipid homeostasis^[10]. Bile acid species and intestinal uptake efficiency, including uptake dependent on the apical sodium-dependent bile acid transporter (ASBT), can dynamically modulate this signaling axis during physiological states such as pregnancy^[72].

As a key downstream effector of FXR, FGF19/15 is synthesized and released into the bloodstream and acts on the liver via portal circulation^[73]. In hepatocytes, FGF19/15 binds FGFR4 and KLB, activating downstream pathways such as Ras/MAPK and PI3K/AKT to suppress the expression of the bile acid synthesis rate-limiting enzyme CYP7A1^[11]. This “gut senses bile acids - FXR induces FGF19/15 - liver receives signal - inhibits bile acid synthesis” enterohepatic axis forms a core negative feedback loop for systemic bile acid and metabolic homeostasis.

Upon binding to FGFR4/KLB, FGF19/15 primarily activates the Ras/MAPK/ERK and PI3K/AKT pathways, the tissue- and context-dependent activation of which governs a wide range of physiological and pathological processes^[74]. Rather than acting through PI3K or c-Jun N-terminal kinase (JNK) alone, FGF19/FGFR4 can phosphorylate ELK1 to drive the expression of the transcription factor ETV4, thereby regulating oncogenes^[75]. In physiological metabolic regulation, intestinal FXR-derived FGF19/15 reaches the liver via the circulation and strongly suppresses CYP7A1 expression through MAPK pathway activation, thereby maintaining bile acid homeostasis^[76].

In contrast, the PI3K/AKT pathway is a critical downstream effector of FGF19 in tumor-related contexts. In cholangiocarcinoma, FGF19 promotes cancer cell proliferation, migration, invasion, and resistance to apoptosis via PI3K/AKT activation^[77]. This pro-tumorigenic mechanism also informs therapeutic strategies; the multi-kinase inhibitor lenvatinib exerts anti-tumor effects by downregulating FGF19 expression and inhibiting PI3K/AKT phosphorylation, with functional studies confirming this axis as a key mediator of lenvatinib efficacy^[77]. In summary, the precise regulation and crosstalk of these pathways determine the cellular fate and systemic metabolic outcomes, providing a theoretical foundation for drug development.

Physiological FGF19/15 signaling is constrained by the FXR-FGF19/15-FGFR4/KLB-CYP7A1 negative-feedback loop described above^[9].

However, in the tumor microenvironment, homeostatic regulation is disrupted and replaced by self-reinforcing positive feedback loops and mechanisms that resist signal termination. For instance, in HCC, FGF19 drives the expression of the transcription factor ETV4 via the FGFR4/ERK pathway, while ETV4 transactivates FGFR4 transcription, forming an FGF19-ETV4-FGFR4 positive feedback loop that amplifies signaling and drives tumor progression^[75]. Concurrently, activated FGFR4 signaling also resists cell death through downstream metabolic reprogramming. In breast cancer resistance models, it suppresses ferroptosis by activating the β-catenin/TCF4 axis and upregulating SLC7A11 and FPN1, thereby ensuring cancer cell survival^[78]. These mechanisms collectively contribute to the widespread failure of signal termination in cancer, highlighting the clinical value of targeting this pathway with FGFR4 inhibitors. The tissue-specific signaling characteristics and therapeutic strategies targeting the FGF19/15 pathway are summarized in Figure 3.

Preclinical studies have provided a foundation for the metabolic benefits of engineered FGF19 analogs. Aldafermin suppresses the key hepatic bile acid-synthesizing enzyme CYP7A1, reduces hepatic bile acid load, and improves steatosis and fibrosis-related features in experimental models. Clinical development of aldafermin illustrates both the promise and complexity of FGF19 agonism. In an early multicenter phase 2 trial, NGM282 improved liver fat content and biological markers in patients with NASH (now termed MASH)^[81]. In the ALPINE 2/3 phase 2b trial, aldafermin was generally well tolerated and improved several secondary endpoints, but it did not meet the primary dose-response endpoint for fibrosis improvement without worsening of NASH (now termed MASH)^[84]. In contrast, the ALPINE 4 trial in patients with NASH (now termed MASH)-related compensated cirrhosis reported significant improvement in the Enhanced Liver Fibrosis score at 48 weeks, supporting continued interest in selected advanced liver disease populations^[80]. These mixed results suggest that FGF19 analog development may require refined disease-stage selection, validated noninvasive endpoints, and careful monitoring of lipid and bile-acid-related safety.

In addition, the FGF19-apolipoprotein A-I chimera Fibapo has shown potential beyond metabolic regulation in various liver injury models. In acetaminophen-induced liver injury and partial hepatectomy models in aged mice, Fibapo not only reduced serum liver enzyme levels but also markedly promoted hepatocyte proliferation and liver regeneration, improving survival rates. These findings provide a preclinical basis for potential application in acute liver failure and regeneration-impaired diseases^[26]. An emerging preclinical strategy uses liver-targeted lipid nanoparticles (LNPs) encoding non-mitogenic FGF19 mRNA; in a diet-induced MASH model, NM-FGF19-mRNA-LNP treatment improved steatosis and metabolic parameters without worsening fibrosis^[85-87].

In oncology, antagonizing the FGF19/FGFR4 signaling axis has attracted significant attention. Extensive preclinical models have confirmed that, in HCC with aberrant activation of FGF19 signaling, FGFR4 small-molecule inhibitors such as BLU-554/fisogatinib, FGF401/roblitinib, H3B-6527, INCB062079, and irpagratinib can block downstream signaling, including ERK1/2, thereby inhibiting tumor cell proliferation and invasion while inducing apoptosis^[88-95].

Beyond small-molecule FGFR4 inhibitors, anti-FGF19 antibodies have shown antitumor activity in FGF19-dependent HCC models. N-terminally directed antibody designs may preserve antitumor activity while reducing bile-acid-related toxicity.

BLU-554/fisogatinib, a highly selective oral FGFR4 inhibitor, was evaluated in a first-in-human phase I trial in patients with advanced HCC using FGF19 immunohistochemistry (IHC) as a biomarker for pathway activation. The study established a recommended dose of 600 mg once daily and showed manageable toxicity dominated by gastrointestinal adverse events. Importantly, objective responses were observed in FGF19-positive patients, whereas no response was observed in FGF19-negative patients, supporting the druggability of the FGF19/FGFR4 axis in biomarker-selected HCC^[90,96,97].

Additional FGFR4 inhibitors have broadened the clinical landscape. Roblitinib/FGF401 was evaluated alone and in combination with spartalizumab in patients with HCC or biomarker-selected solid tumors and showed biologically active dosing, manageable safety, and preliminary efficacy^[88]. H3B-6527 entered phase I evaluation in HCC and ICC, with early evidence of antitumor activity in selected patients^[92]. INCB062079, an irreversible FGFR4 inhibitor, demonstrated on-target pharmacodynamic activity but encountered dose-limiting gastrointestinal and hepatobiliary toxicities, emphasizing the need to manage bile acid pathway disruption when blocking FGFR4^[91].

More recent clinical development has focused on biomarker-defined and combination strategies. Irpagratinib/ABSK011 has shown encouraging activity in FGF19-overexpressing advanced HCC in early-phase studies and is being evaluated in combination with atezolizumab; updated phase II data reported objective response rates of 50.0% in the treatment-naive cohort and 52.9% in the previously treated cohort^[93,94]. TYRA-430, an FGFR4/3-biased inhibitor designed for FGF19-positive/FGFR4-driven cancers, has also entered a first-in-human phase I study in advanced HCC and other solid tumors with activating FGF/FGFR pathway aberrations^[98]. These developments indicate that the field is moving from single-agent proof-of-concept studies toward precision oncology approaches combining FGFR4 blockade, immune checkpoint inhibition, and resistance-aware drug design. Because most of these studies are early-phase and biomarker-enriched, the observed response signals require confirmation in larger randomized cohorts. To provide a clearer overview of current translational progress, representative FGF19/15-targeted therapeutic strategies are summarized in Table 2.