Mechanism of FXR signaling: from liver inflammation to hepatocellular carcinoma

Abstract

Objective

To clarify the core regulatory role and molecular mechanism of farnesoid X receptor (FXR) in the progression from liver inflammation/fibrosis to hepatocellular carcinoma (HCC), and to provide a theoretical basis for targeted prevention and treatment of liver diseases.

Methods

A systematic review was performed to integrate FXR's key regulatory mechanisms in bile acid homeostasis, inflammatory signaling, metabolic reprogramming, tumor pathways, and the tumor immune microenvironment. Intervention effects of natural compounds and FXR agonists/antagonists were analyzed for clinical translational potential.

Results

FXR acts as a core regulator throughout the inflammation–fibrosis–HCC axis via bidirectional mechanisms. (1) In inflammation/fibrosis, FXR activation upregulates BSEP, FGF15/19, and SHP, inhibits CYP7A1 to maintain bile acid homeostasis, suppresses the TLR4/NF-κB axis and NLRP3 inflammasome, reduces IL-6/TNF-α, and directly inhibits hepatic stellate cell activation and matrix deposition. Agonists like INT-767 block progression from chronic hepatitis to fibrosis/cirrhosis (2) In HCC, FXR dysfunction (e.g., HBx C40-mediated). causes bile acid accumulation, glucose metabolic disorders, and Notch1/STAT3 activation, driving HCC progression. FXR activation inhibits STAT3 phosphorylation, glycolytic enzymes, and Wnt activity. Quercetin and obeticholic acid suppress tumor growth via FXR signaling. (3) Aberrant FXR signaling correlates with immune microenvironment dysregulation and immune escape. FXR agonists reshape the microenvironment and enhance anti-PD-1 efficacy; combined FXR and GPC3 detection improves HCC diagnostic specificity.

Conclusion

FXR is a central hub regulating the liver inflammation–fibrosis–HCC axis. FXR-targeting agonists, natural compounds, and combination immunotherapy hold significant translational potential. Further studies are needed to clarify FXR's tissue-specific functions and bidirectional mechanisms, and to develop highly selective modulators for precise liver disease prevention and treatment.

Highlights

• •FXR maintains BA homeostasis & suppresses inflammation to inhibit liver fibrosis & HCC.
• •FXR deficiency promotes HCC via metabolic reprogramming & STAT3/Wnt activation.
• •FXR exerts bidirectional effects depending on cell type, stage, and TME.
• •FXR agonists combined with anti-PD-1 therapy show potent anti-HCC efficacy.

Graphical Summary Description

This figure visually summarizes the core mechanisms of the study, illustrating FXR as a master hub regulating the progression from liver inflammation/fibrosis to HCC, along with targeted intervention strategies. The core logic is organized into four levels. The main content of the artical has been demonstrated through Fig. 1.

Fig. 1.

The core regulatory role and targeted intervention strategies of farnesol X receptor (FXR) in the progression axis of liver inflammation, liver fibrosis, and hepatocellular carcinoma

(Note: in the figure, ↑ represents the upregulation of molecular expression or the enhancement of biological effect, ↓ represents the downregulation of molecular expression or the inhibition of biological effect, ├ represents the inhibition of signal pathway; abbreviation notes: BA (bile acid), ECM (extracellular matrix), HSC (hepatic stellate cell), TME (tumor immune microenvironment), OCA (obeticholic acid)).

1. Core regulatory positioning.

FXR is a master regulator of hepatic metabolism, inflammation, fibrosis, and hepatocyte malignant transformation. Its functional status determines chronic liver disease progression and outcomes, making FXR the central target.

2. Gut–liver axis coordination.

Intestinal FXR activation upregulates FGF15/19, which acts on the liver via portal circulation to maintain bile acid homeostasis, suppress NLRP3 and TLR4/NFκB axes, reduce IL6/TNFα release, and block liver inflammation initiation and amplification (see Sections 1.1–1.2).

3. Stagespecific regulation.

Fibrotic stage:FXR activation inhibits hepatic stellate cell (HSC) activation and ECM deposition, upregulates BSEP/SHP to maintain bile acid homeostasis, breaking the inflammation–fibrosis cycle (see Chapter 2).

Tumor stage:FXR exerts direct tumor suppression by inhibiting STAT3 phosphorylation, Wnt signaling, glycolytic enzymes, and Notch1 activation. It also reshapes the tumor immune microenvironment (TME) and reverses norcamediated immune escape. Combining FXR activation with antiPD1 antibodies produces synergistic antitumor effects (see Chapter 3).

4. Targeted intervention strategies.

This level identifies synthetic FXR agonists (OCA, INT767) and natural compounds (quercetin, ginsenosides) with their applicable stages, providing a translational direction for preventing and treating chronic liver disease and HCC, consistent with the clinical value of targeting FXR.

1. Introduction

As a malignant tumor, liver cancer is characterized by high incidence and mortality rates, ranking as the sixth most commonly diagnosed cancer worldwide and the third leading cause of cancer-related deaths [1]. Hepatocellular carcinoma (HCC) represents the predominant pathological type of liver cancer, accounting for 75%-85% of cases [2]. Diverse risk factors contribute to HCC development, including Hepatitis B Virus (HBV) infection, Hepatitis C Virus (HCV) infection, chronic excessive alcohol consumption, metabolic dysfunction-associated steatotic liver disease (MASLD), diabetes mellitus, nitrite intake, and aflatoxin exposure [3,4]. The progression of HCC typically follows a pattern from chronic liver disease to end-stage malignancy, generally evolving from chronic hepatitis to liver fibrosis, progressing to cirrhosis, and ultimately culminating in HCC. However, treatment options after HCC diagnosis are limited and ineffective [5]. Surgical resection is generally the primary approach, though only patients in stages Ia-IIb are eligible for surgical intervention. Postoperative adjuvant therapy with antitumor drugs is employed, yet no significant improvement in 5-year survival rates has been observed. Alternative therapies, including radiofrequency ablation, cryotherapy, focused ultrasound, and radiation therapy, may also be utilized for some patients [6]. Nevertheless, long-term clinical studies have revealed that while these methods can modestly extend survival, their effectiveness in improving patient prognosis remains suboptimal. Therefore, exploring novel therapeutic approaches represents an ongoing and enduring endeavor

Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily, governed by nuclear receptor subfamily 1, group H, member 4 (NR1H4). In humans, it is encoded by two genes, FXRα and FXRβ [7]. The FXRαgene encodes four isoforms: FXRα1, FXRα2, FXRα3, and FXRα4. Expression of FXRα1and FXRα2 are most abundant in the liver, while FXRα3 and FXRα4 are most prevalent in the intestine and kidneys [8]. FXR receptors are primarily expressed in the liver, small intestine, kidneys, and heart. By modulating pathways involved in glucose and fatty acid metabolism, FXR plays a crucial biological role in maintaining cholesterol and bile acid (BA) homeostasis, suppressing hepatic inflammation, and promoting liver regeneration and repair following liver injury [9,10]. FXR exhibits tissue-specificity and intricate mechanisms in regulating metabolic diseases and hepatocellular carcinoma (HCC). This article will discuss the mechanisms of FXR in hepatic inflammation and HCC, aiming to provide insights for future research into the treatment of liver inflammation and HCC, thereby guiding future therapeutic strategies for this disease.

2. Study on the mechanism of FXR in liver inflammation

When discussing liver inflammation, the most common types include viral hepatitis (caused by HBV and HCV), autoimmune hepatitis, MASLD, and metabolic dysfunction-associated steatohepatitis (MASH). Viral hepatitis remains a major global health problem, with related studies finding that HBV infects approximately 296 million people worldwide, and HCV infects approximately 58 million people [11]. Related epidemiological studies have found that the annual incidence of autoimmune hepatitis in Europe and North America is around 1-2 cases per 100,000 individuals [12]. MASLD, now a public health threat, currently affects more than 35% of the global adult population [13]. It is projected that by 2040, more than 50% of the global adult population will be estimated to have MASLD [14].

2.1. Regulation of bile acid homeostasis by FXR

FXR is a nuclear receptor primarily expressed in the liver and intestines and is essential for maintaining bile acid (BA) homeostasis. BAs act as agonists for FXR. Additionally, BAs play a crucial role in the digestion and absorption of fats, and their excessive accumulation can lead to oxidative stress and liver injury.

FXR maintains bile acid (BA) homeostasis through the following mechanisms. First, it directly regulates BA efflux. FXR binds to the promoter region of the bile salt export pump (BSEP) gene, upregulates BSEP expression, promotes BA efflux from hepatocytes into the bile duct, and reduces intracellular BA accumulation [15]. Second, it inhibits BA synthesis. Upon activation, FXR induces the expression of the small heterodimer partner (SHP), which acts as a transcriptional repressor to directly inhibit cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in BA synthesis, thereby reducing de novo BA synthesis and functionally synergizing with BSEP-mediated BA efflux [16]. Third, it coordinates cross-organ regulation via the gut–liver axis. Following activation by BA in ileal enterocytes, intestinal FXR binds to the promoter region of fibroblast growth factor 19 (FGF19 in humans; FGF15 in mice), promoting its transcription and secretion. FGF19/15 enters the liver through the portal vein and binds to the FGFR4/β-Klotho receptor complex on the hepatocyte membrane, activating the downstream MAPK/ERK pathway, which further suppresses CYP7A1 expression, thereby achieving coordinated BA homeostasis via the gut–liver axis [[17], [18], [19]]. Fourth, it synergistically regulates oxidative stress. FXR and nuclear factor erythroid 2-related factor 2 (Nrf2) interact in the regulation of hepatic oxidative stress and inflammation: Nrf2 primarily mediates reactive oxygen species (ROS) detoxification and repair of oxidative damage, whereas FXR reduces BA-induced oxidative stress triggers by maintaining BA homeostasis. Together, they alleviate liver oxidative damage [20]. Of note, certain compounds can disrupt BA metabolism and induce liver injury by inhibiting the FXR pathway. For instance, oleanolic acid suppresses FXR-mediated BSEP expression, leading to impaired BA efflux and disruption of tight junctions in hepatocytes, thereby inducing liver injury [21], which conversely validates the central role of FXR in maintaining BA homeostasis.

Through the above mechanisms, FXR maintains BA homeostasis, which serves as the core foundation for its hepatoprotective and anti-inflammatory effects. Relevant pharmacological intervention studies further confirm the therapeutic value of this pathway in the treatment of liver inflammation.

2.2. Regulatory mechanism of FXR on inflammation

As a core nuclear receptor governing bile acid metabolism, FXR suppresses hepatic inflammation through two complementary mechanisms: (i) a direct mechanism, whereby FXRphysically interacts with—or transcriptionally regulates—key components of core inflammatory signaling pathways; and (ii) an indirect mechanism, whereby FXR restrains inflammation by acting on upstream intermediates, including maintenance of bile acid homeostasis, remodeling of bile acid synthesis, cooperation with other nuclear receptors, and regulation ofdownstream metabolic target genes. Accordingly, this section is organized along these two dimensions and summarizes the corresponding pharmacological evidence for each.

2.2.1. FXR exerts anti-inflammatory effects by directly regulating inflammatory signaling pathways

FXR can directly interact with, or transcriptionally target, key molecules within core inflammatory signaling pathways, thereby suppressing the activation and propagation of inflammatory cascades. This constitutes the direct mechanism of its anti-inflammatory activity and mainly involves the following pathways.

NF-κB/NLRP3 inflammatory signaling pathway.

Nuclear factor κB (NF-κB) serves as the central transcription factor in inflammatory responses, while the NLRP3 inflammasome acts as a key amplifier of the inflammatory cascade. Their synergistic action drives the progression of chronic liver inflammation. FXR can directly interact with the p65 subunit of NF-κB, inhibiting its nuclear translocation and transcriptional activity, thereby downregulating the expression of downstream pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Concurrently, FXR suppresses the phosphorylation and activation of the NLRP3 inflammasome, blocking the maturation and release of pro-inflammatory factors and consequently alleviating liver inflammatory injury.

Pharmacological evidence supports these mechanisms. Wedelolactone (WED), an extract from Eclipta prostrata, activates FXR to regulate bile acid metabolism and modulate the NF-κB/Nrf2 signaling axis, thereby ameliorating hepatotoxicity and inflammation associated with bile acid accumulation [22,23]. Xiaoyao Powder Granules target the FXR/NLRP3 pathway, inhibit NLRP3 inflammasome activation, reverse hepatic inflammation, and mitigate MASH-related injury [24]. Furthermore, FXR overexpression directly blocks NLRP3 inflammasome activation, improving lipid metabolism and hepatic steatosis in mice fed a high-fat diet [22].

Wnt/β-catenin inflammatory regulatory axis.

Aberrant activation of the Wnt/β-catenin signaling pathway exacerbates cholestasis-induced liver inflammation by potentiating the NF-κB-dependent inflammatory axis. As a key upstream regulator, FXR directly modulates Wnt pathway activity, thereby inhibiting downstream inflammatory cascades. Studies have demonstrated that Wnt signaling inhibition disrupts the NF-κB-dependent inflammatory axis and reduces cholestasis-induced liver inflammation [[25], [26], [27], [28]]. Additionally, pirfenidone suppresses the Wnt/GSK-3β/β-catenin pathway by modulating FXR signaling, thereby blocking downstream NF-κB/TNF-α-mediated inflammatory signaling and alleviating ANIT-induced cholestatic liver injury [29].

2.2.2. FXR suppresses inflammatory responses through indirect mechanisms

Beyond directly targeting inflammatory pathways, FXR more broadly restrains hepatic inflammation in an indirect manner—by correcting bile acid metabolic disturbances, remodeling bile acid synthesis, cooperating with other nuclear receptors, and regulating downstream metabolic effector genes. In each case, FXR does not act on the inflammatory machinery itself but instead eliminates or attenuates upstream inflammatory triggers.

FXR suppresses inflammation by maintaining bile acid homeostasis.

Excessive bile acid accumulation serves as a primary trigger for oxidative stress and inflammatory injury in the liver. FXR exerts its anti-inflammatory effects primarily by preserving the homeostasis of bile acid synthesis, efflux, and enterohepatic circulation, thereby mitigating bile acid-mediated inflammation at its origin. The core mechanism of this pathway lies in correcting bile acid metabolic disorders and eliminating endogenous inflammatory triggers, subsequently blocking the initiation of inflammatory cascades.

Numerous pharmacological studies have substantiated the anti-inflammatory effects of targeted interventions within this regulatory framework. For instance, Sangyu Granules, a traditional Chinese medicine formulation, maintain hepatobiliary circulation balance by modulating key proteins involved in bile acid secretion, thereby significantly ameliorating drug-induced liver injury-associated inflammation [30]. Salidroside corrects bile acid metabolic disturbances and alleviates hepatic inflammation and steatosis in MASH model mice through activation of the BA-FXR/TGR5 signaling pathway [31]. Isorhamnetin promotes bile acid efflux and alleviates bile acid retention by upregulating the FXR/BSEP signaling axis, indirectly exerting anti-inflammatory effects following the restoration of metabolic homeostasis [15]. Ginsenoside Rh4 activates FXR, upregulates downstream SHP expression, inhibits CYP7A1 and CYP8B1 transcription, reduces bile acid synthesis, and consequently improves hepatic lipid metabolism and inflammation [32]. Silibinin maintains bile acid balance and exerts hepatoprotective effects by inhibiting HDAC2 activity, enhancing histone acetylation in the FXR promoter region, and upregulating intestinal FGF15/19 expression [33]. Pirfenidone reverses the downregulation of FXR and BSEP expression induced by α-naphthyl isothiocyanate (ANIT), restores bile acid efflux function, and alleviates cholestatic liver injury and inflammatory responses [29]. Glycyrrhizin promotes bile acid efflux via the Nrf2/FXR-BSEP signaling axis while modulating the gut microbiota to alleviate hepatic inflammation and oxidative stress [20]. Furthermore, the environmental toxin bisphenol A induces bile acid metabolic disorders and hepatic steatosis by inhibiting the microbiota-BA-FXR/TGR5 signaling pathway, further confirming the central role of FXR-mediated bile acid homeostasis in regulating liver inflammation [34].

FXR suppresses the TLR4/MYD88/JNK pathway by modulating primary bile acid synthesis.

Toll-like receptor 4 (TLR4)-mediated innate immune activation is a critical initiator of hepatic inflammation, and excessive activation of the downstream MYD88/JNK axis promotes the transcription and release of pro-inflammatory cytokines. Rather than acting on this axis directly, FXR suppresses it indirectly by remodeling bile acid metabolism: by modulating primary bile acid synthesis, FXR reduces the availability of endogenous bile-acid–derived TLR4 ligands, thereby dampening downstream signal transduction. This indirect route is supported by pharmacological evidence: the flavonoid 7-O-α-l-rhamnopyranosyl-quercetin-3-O-β-d-glucopyranoside (KGR) activates FXR signaling by modulating primary bile acid synthesis, thereby suppressing the TLR4/MYD88/JNK pathway, reducing oxidative stress and inflammatory responses in Con A-induced autoimmune hepatitis mice, and lowering serum transaminases as well as pro-inflammatory cytokines including IL-6 and TNF-α [35].

FXR indirectly modulates inflammation via synergy with other nuclear receptors.

As an indirect anti-inflammatory route, FXR forms a synergistic regulatory network with other nuclear receptors within the same family to jointly maintain hepatic metabolic homeostasis and suppress metabolism-related inflammatory responses, with the most pronounced synergy observed with liver X receptors (LXRs). LXRs (LXRα/β) also belong to the nuclear hormone receptor superfamily [36] and exhibit significant anti-inflammatory and metabolic regulatory activities. They display functional complementarity and synergy with FXR in the regulation of hepatic lipid and bile acid metabolism. Dual activation of FXR and LXR can simultaneously correct metabolic disturbances and inhibit inflammatory activation, thereby achieving comprehensive intervention in metabolism-related fatty liver disease.

Pharmacological studies have substantiated these effects. Broccoli extract has been shown to reduce the levels of inflammatory factors (IL-1β, IL-6, TNF-α) and insulin in MAFLD mice by modulating the FXR/LXR pathway, while enhancing the body's antioxidant capacity, thus comprehensively improving hepatic metabolism and inflammatory status [37]. In addition, hederagenin A, a dual LXR/FXR receptor activator, significantly ameliorates NAFLD-related hepatic inflammation in both mouse models and in vitro cellular experiments [38].

FXR indirectly regulates inflammation through downstream target genes.

FXR further restrains inflammation indirectly by transcriptionally regulating downstream effector genes that couple metabolism to inflammation. Lipocalin 13 (LCN13) is a key downstream effector of FXR. Belonging to the lipocalin family [39], LCN13 is expressed in various tissues including the liver and pancreas, where it modulates cellular metabolism, proliferation, and inflammatory responses [40,41]. Its expression is regulated by nutritional status and glucose levels [42] and is markedly suppressed under high-fat diet conditions.

Studies have demonstrated that FXR directly activates LCN13 transcription. Overexpression of LCN13 significantly ameliorates lipid accumulation and inflammatory responses in hepatocytes, whereas LCN13 knockdown exacerbates the MASH phenotype. These findings indicate that LCN13 serves as a critical effector molecule downstream of FXR in regulating hepatic inflammation and metabolic homeostasis [43]. This discovery provides a novel mechanistic insight into FXR-mediated metabolic-inflammatory crosstalk and identifies a promising downstream target for therapeutic intervention.

Collectively, the integrated roles of FXR in bile acid homeostasis, inflammation regulation, and related intervention strategies are summarized in Table 1.

Table 1.

Integrated role of FXR in bile acid homeostasis, inflammation regulation, and intervention strategies.

Category	Core mechanism	Key pathways/factors	Functional effects	References
Regulation of bile acid homeostasis	Direct promotion of BA efflux	FXR↑ → BSEP↑	Alleviates BA retention, restores metabolic homeostasis	[15,32,35]
	Inhibition of de novo BA synthesis	FXR↑ → SHP↑ → CYP7A1↓	Reduces BA production	[17,29]
	Gut–liver axis crosstalk	Intestinal FXR↑ → FGF15/19↑ → Hepatic FGFR4/β-Klotho → CYP7A1↓	Reduces hepatic BA load	[19,20,34]
	Synergistic antioxidant effect	FXR–Nrf2 interplay	Attenuates BA-induced oxidative stress	[21,29]
Inflammatory regulation	Direct anti-inflammatory mechanisms	—	—	—
	Direct suppression of NF-κB/NLRP3 inflammatory axis	FXR binds NF-κB p65 → nuclear translocation↓; NLRP3 phosphorylation↓	Blocks inflammatory cascade, reduces IL-1β, IL-6, TNF-α release, alleviates liver injury	[22,24,28,29]
	Direct modulation of Wnt/β-catenin regulatory axis	FXR → Wnt/GSK-3β/β-catenin↓ → downstream NF-κB/TNF-α↓	Inhibits NF-κB-dependent inflammatory axis, alleviates cholestatic liver injury	[[25], [26], [27], [28], [29]]
	— Indirect anti-inflammatory mechanisms —	—	—	—
	Eliminates inflammatory triggers via maintaining BA homeostasis	FXR → BSEP↑/CYP7A1↓ → BA retention↓	Blocks inflammatory cascade initiation at source by correcting BA metabolic disorders	[15,30,32]
	Inhibits TLR4/MYD88/JNK pathway via remodeling primary BA synthesis	FXR → primary BA synthesis profile alteration → endogenous TLR4 ligand availability↓ → MYD88/JNK↓	Reduces pro-inflammatory cytokine levels, ameliorates autoimmune hepatitis-related liver injury	[35]
	Synergistic anti-inflammation via cooperation with other nuclear receptors	Dual activation of FXR/LXR	Simultaneously corrects metabolic disturbances and inhibits inflammatory activation, improves MASLD phenotype	[37,38]
	Regulates metabolic-inflammatory crosstalk via downstream target genes	FXR → LCN13 transcription↑	Ameliorates hepatocyte lipid accumulation and inflammatory responses	[43]
Pharmacological interventions and functional validation	Modulation by natural compounds and drugs	Sangyu Granules, salidroside, isorhamnetin, ginsenoside Rh4, silibinin, pirfenidone, glycyrrhizin	Restores BA homeostasis, reduces inflammation and oxidative stress, alleviates liver injury	[[29], [30], [31], [32], [33], [34]]
	Reverse toxicity validation	Oleanolic acid → FXR↓ → BSEP↓ → impaired BA efflux	Induces cholestasis and liver injury, validates the central role of FXR in BA homeostasis	[21]
	Environmental toxin validation	Bisphenol A → microbiota–BA–FXR/TGR5 signaling↓	Induces hepatic steatosis and inflammation, confirms FXR-mediated anti-inflammatory effect	[22,34]

3. Mechanisms of FXR in hepatic fibrosis and cirrhosis

Hepatic fibrosis/cirrhosis originates from chronic hepatitis, with its staging closely associated with all-cause and liver-related mortality [44]. The pathogenesis and progression of this condition are fundamentally linked to hepatic stellate cells (HSCs) [45]. Under chronic inflammatory conditions, quiescent HSCs activate into myofibroblasts that secrete excessive extracellular matrix (ECM) [46], thereby establishing themselves as core therapeutic targets. Pathological ECM deposition disrupts hepatic architecture and perpetuates inflammatory stimulation [47]. Activated HSCs serve as the primary source of key collagen types (I, III, V) during advanced fibrogenesis [48].

3.1. FXR regulation of HSC activation and ECM metabolism

The core mechanism of hepatic fibrosis is intimately associated with hepatic stellate cell (HSC) activation. FXR activation not only suppresses HSC activation (thereby reducing the source of ECM production) but also directly regulates key genes involved in extracellular matrix (ECM) synthesis and degradation, promoting ECM degradation while inhibiting pathological deposition [49]. Targeting this process, multiple studies have focused on anti-fibrotic strategies directed at HSCs. Research demonstrates that the FXR agonist INT-767 modulates ECM metabolism in HSCs, providing a novel therapeutic direction for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis [50]; Angelica sinensis extract (AD) and its constituent bergamottin (BG) significantly reduce ECM accumulation and alleviate CCl₄-induced hepatic fibrosis in mice by upregulating FXR expression and inhibiting Caspase-1/IL-1β [51]. Raspberry ketone (RK), an aromatic compound first isolated from raspberries, suppresses ECM accumulation, inflammation, and epithelial-mesenchymal transition (EMT) processes in activated HSCs, ultimately intervening in fibrotic progression [52].

3.2. FXR-mediated regulation of inflammation and apoptosis

Inflammation plays a pivotal role in hepatic fibrogenesis. FXR exerts inhibitory effects on the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, whose activation triggers pro-inflammatory cytokine release and inflammatory cell death [53]. FXR suppresses NLRP3 activity through multiple mechanisms: Zhang et al. discovered that Zbtb18 inhibits the NLRP3 inflammasome by activating FXR-mediated fatty acid oxidation (FAO) and clathrin heavy chain (CLTC) expression, thereby alleviating inflammatory stress and insulin resistance [54]. The traditional Chinese formula Xiaoyaosan Granules reverses hepatic inflammation and suppresses NASH-associated inflammation by targeting the FXR/NLRP3 signaling pathway [24]. Xu et al. demonstrated that FXR overexpression blocks NLRP3 activation and improves lipid metabolism with hepatic steatosis in high-fat diet-fed mice [22]. NLRP3 inflammasome activation correlates with bile acid (BA) metabolic dysregulation, whereas FXR reduces its activity by inhibiting NLRP3 phosphorylation, consequently mitigating fibrosis [55]. The PI3K/AKT pathway influences fibrotic progression by regulating cellular proliferation and apoptosis. Studies confirm that the classical formula Sinisan inhibits hepatocyte apoptosis and ameliorates CCl₄-induced fibrosis by downregulating the p-PI3K/PI3K and p-AKT/AKT expression ratios while increasing FXR expression [56].

3.3. FXR-bile acid metabolic axis and gut-liver axis

FXR-mediated regulation of bile acid (BA) metabolism constitutes a crucial anti-fibrotic mechanism. Melatonin reduces inflammation and fibrosis in cadmium (Cd)-exposed mice by remodeling gut microbiota and activating intestinal FXR signaling to suppress hepatic BA synthesis [57]. Paradoxically, the FXR agonist obeticholic acid (OCA) may exacerbate liver injury in cholestatic patients by inducing hepatocyte apoptosis through hepatic FXR activation, while ileum-specific FXR knockout experiments suggest intestinal FXR represents a safer target for BA modulation [58]. Research by Fuchs et al. demonstrates that glucagon-like peptide (GLP)-2 promotes intestinal FXR-FGF15/19 signaling, resulting in decreased Cyp7a1 and increased Cyp2c70 expression in the liver, thereby mediating GLP-2's anti-fibrotic effects on hepatic stellate cells (HSCs) in mice [59]. Moreover, dysregulation of FXR-FGF19 signaling may exacerbate cirrhosis progression, establishing a vicious cycle of BA retention, gut barrier disruption, and bacterial translocation [60].

3.4. Novel FXR-targeted therapeutic strategies

It was found that knockdown of Fincor (FXR-induced non-coding RNA) attenuates the inhibitory effects of the FXR agonist tropifexor on fibrosis markers (e.g., Col1a1) and inflammatory cytokines (e.g., IL-1β), while reversing its regulatory actions on apoptosis-related genes [61]. Raspberry ketone (RK) reverses hepatic stellate cell (HSC) activation through dual-target synergistic activation of FXR/PGC-1α, with its anti-fibrotic effects being significantly diminished upon FXR or PGC-1α deficiency [52]. Furthermore, the novel compound 3a, functioning as a dual LIFR inhibitor/FXR agonist, concurrently suppresses acute fibrogenesis and inflammatory development [62].

The specific content of FXR mechanisms in hepatic fibrosis and cirrhosis has been presented in the form of a table, specifically Table 2.

Table 2.

Mechanisms of action and therapeutic strategies of FXR in hepatic fibrosis and cirrhosis.

Category	Core mechanism	Key pathways/factors	Functional effects/clinical implications	References
Regulation of HSC activation and ECM metabolism	Suppresses HSC activation and modulates ECM turnover	FXR activation → HSC quiescence; INT-767 regulates ECM metabolism	Reduces pathological ECM deposition, blocks myofibroblast transdifferentiation, alleviates MASH-related fibrosis	[49,50]
	Upregulates FXR and inhibits Caspase-1/IL-1β axis	Angelica sinensis extract bergamottin (BG)	Reduces ECM accumulation, attenuates CCl4-induced hepatic fibrosis	[51]
	Dual-target synergistic activation of FXR/PGC-1α	Raspberry ketone (RK); inhibits ECM accumulation, inflammation and EMT	Reverses HSC activation and blocks fibrotic progression	[52]
Regulation of inflammation and apoptosis	Inhibits NLRP3 inflammasome activation	Zbtb18 → FXR-mediated FAO and CLTC upregulation; FXR/NLRP3 pathway	Alleviates inflammatory stress and insulin resistance, suppresses fibrogenesis	[54,55]
	Inhibits PI3K/AKT pathway to reduce hepatocyte apoptosis	Sinisan formula; downregulates p-PI3K/PI3K and p-AKT/AKT ratios	Ameliorates CCl4-induced hepatic fibrosis via anti-apoptotic effect	[56]
Bile acid metabolism and gut–liver axis regulation	Activates intestinal FXR via gut microbiota remodeling	Melatonin; intestinal FXR → FGF15/19 → hepatic BA synthesis suppression	Reduces inflammation and fibrosis in cadmium-exposed mice	[57]
	Hepatic FXR activation may exacerbate cholestatic injury	OCA induces hepatocyte apoptosis via hepatic FXR; ileal FXR is a safer target	Reveals tissue-specific differences of FXR and safety risk in cholestasis	[58]
	GLP-2 enhances intestinal FXR-FGF15/19 signaling	GLP-2→ decreased Cyp7a1, increased Cyp2c70 in liver	Exerts anti-fibrotic effects on hepatic stellate cells	[59]
	Dysregulated FXR-FGF19 signaling exacerbates cirrhosis	BA retention, gut barrier disruption, bacterial translocation	Forms a vicious cycle driving cirrhosis progression	[60]
Novel FXR-targeted therapeutic strategies	FXR-induced lncRNA Fincor mediates anti-fibrotic efficacy	Fincor knockdown attenuates tropifexor's effect on Col1a1 and IL-1β	Enhances the anti-fibrotic and anti-inflammatory effects of FXR agonists	[61]
	Dual LIFR inhibitor/FXR agonist suppresses fibrogenesis	Novel compound 3a; concurrent inhibition of acute fibrosis and inflammation	Provides a novel dual-target strategy for hepatic fibrosis treatment	[62]

4. Research on FXR-related mechanisms in hepatocellular carcinoma

FXR exerts dual regulatory roles in HCC pathogenesis, though its mechanisms remain incompletely understood. The following discussion examines emerging evidence regarding how FXR influences hepatocarcinogenesis through metabolic reprogramming, tumor-associated signaling pathways, and immune microenvironment modulation, thereby exploring the translational potential of FXR-targeted diagnostic and therapeutic strategies for HCC.

4.1. The central role of FXR in regulating metabolic homeostasis in HCC

4.1.1. Reprogramming of glucose metabolism

As a bile acid-activated nuclear receptor, FXR regulates multiple cellular processes via transcriptional control [63]. Beyond bile acid homeostasis, it serves as a key modulator of hepatic glucose metabolism in both physiological and tumorigenic contexts.

Physiologically, FXR maintains glucose homeostasis mainly by suppressing hepatic gluconeogenesis. Activated FXR upregulates small heterodimer partner (SHP), which represses forkhead box O1 (FOXO1) and hepatocyte nuclear factor 4α (HNF4α), thereby downregulating the rate-limiting gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) to reduce hepatic glucose output [16,64]. Concurrently, FXR inhibits NF-κB signaling and lowers pro-inflammatory cytokines IL-6 and TNF-α, alleviating cytokine-induced insulin resistance and reducing hepatocarcinogenesis risk [65,66].

During hepatocarcinogenesis, FXR deficiency drives glycolytic reprogramming (the Warburg effect). Functional FXR transcriptionally represses core glycolytic enzymes to limit energy supply for tumor proliferation. Zhong et al. confirmed that quercetin exerts FXR-dependent anti-HCC effects by downregulating hexokinase 2 (HK2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase A (LDHA), and disrupting glycolysis/gluconeogenesis metabolite profiles; these effects are significantly attenuated upon FXR knockdown [67].

In HBV-related HCC, FXR is often downregulated or dysfunctional. The C-terminally truncated HBx variant HBx C40 synergizes with FXR deficiency to promote HCC progression by impairing FXR activity, relieving inhibition of HK2 and activating the glycolysis/gluconeogenesis pathway [68]. Notably, full-length HBx functions as an FXR coactivator and suppresses HCC, whereas truncated variants (e.g., HBx-C30, HBx-C40) fail to activate FXR and may even disrupt its normal function, exerting pro-tumor effects [69].

4.1.2. Bile acid homeostasis and epigenetics

Thymine DNA glycosylase (TDG), a nuclear receptor coactivator, plays a critical role in maintaining cellular epigenetic stability. Research by Haider M. Hassan et al. revealed that deletion of the gene encoding TDG disrupts the regulatory cascade between the farnesoid X receptor (FXR) and the small heterodimer partner (SHP). This dysregulation leads to bile acid (BA) accumulation and glucose metabolism disorders, culminating in an increased risk of hepatocellular carcinoma (HCC) [70,71]. The same team further demonstrated that FXR deficiency acts as a key driver of HCC development. FXR deficiency synergizes with BA overload, circadian rhythm disruption, and dysregulation of insulin signaling pathways to promote hepatocarcinogenesis. Notably, FXR itself exerts hepatoprotective effects by mitigating the impact of BA overload, which is recognized as a major pathogenic factor in HCC [72].

Defects in the ABCB11 gene (encoding the bile salt export pump BSEP) constitute another key mechanism disrupting bile acid (BA) homeostasis. BSEP serves as a critical regulator for maintaining BA homeostasis. In Abcb11 mouse models, cholestatic liver injury and hepatic tumorigenesis resulting from BSEP deficiency are associated with elevated levels of BAs possessing FXR-antagonistic activity. These antagonistic BAs suppress normal FXR activation [73].

Additionally, FXR inhibits HCC progression by activating the Hippo signaling pathway through induction of fibroblast growth factor 15 (FGF15). Specifically, FXR induces FGF15 production in ileal cells, and FGF15 subsequently activates Hippo signaling in the liver. This pathway ultimately suppresses bile acid metabolism, prevents hepatic hyperplasia, and inhibits HCC development [74].

4.2. Direct regulation of tumor-associated signaling pathways by FXR

4.2.1. STAT3-CSCs axis

Signal transducer and activator of transcription 3 (STAT3), the most extensively studied member of the STAT family, exhibits constitutive activation in most human cancers and is frequently associated with poor clinical prognosis [75]. Substantial experimental evidence further indicates that STAT3 is closely linked to cancer stem cells (CSCs) [76].

Building on previous findings that FXR suppresses digestive system tumors by inhibiting STAT3 phosphorylation through upregulation of SOCS3 expression [77], Ye et al. specifically investigated FXR in liver CSCs. Their study revealed that FXR-mediated targeting of SOCS3 inhibits STAT3 phosphorylation, thereby suppressing CSCs [78]. Junhua Gong et al. demonstrated that the FXR antagonist T-β-MCA inhibits the FXR/SHP pathway and amplifies the pro-apoptotic effects of P53-induced activation of the P53/miR-34a/SIRT1 positive feedback loop both in vitro and in vivo [79].

4.2.2. EMT and metastasis-associated pathways

Activation of epithelial-mesenchymal transition (EMT) is a critical process in cancer metastasis, during which epithelial cells acquire mesenchymal characteristics with enhanced motility and migratory capacity. Studies confirm that FXR1 promotes HCC proliferation, migration, and invasion by regulating SMAD2/3 [80]. FXR agonist treatment enhances TGF-β-induced EMT morphological changes, whereas FXR antagonists suppress TGF-β effects. Consequently, FXR activation potentiates EMT in HCC, suggesting FXR antagonists as potential therapeutic candidates for EMT inhibition [81].

Dysregulation of Wnt/β-catenin signaling frequently occurs in human HCC [82]. Shu Feng et al. discovered that α-linolenic acid treatment upregulates FXR expression in HCC cells and progressively reduces β-catenin levels and its downstream target gene cyclin D1, thereby demonstrating suppression of HCC progression via the FXR/Wnt/β-catenin pathway [83].

4.2.3. Metabolic enzymes and immune microenvironment

Studies confirm that acyl-CoA synthetase long-chain family member 4 (ACSL4), a fatty acid metabolism-related enzyme, is a critical player in hepatocellular carcinoma (HCC) progression [84,85]. Wenbiao Che et al. demonstrated that silencing ACSL4 elevates farnesoid X receptor (FXR) expression, reduces bile acid (BA) levels, and impedes M2 macrophage polarization, thereby ameliorating HBV-associated HCC [86].

Transketolase (TKT), a metabolic enzyme in the non-oxidative phase of the pentose phosphate pathway (PPP), plays a vital role in providing precursors for macromolecule biosynthesis in cancer cells [87,88]. Research reveals that TKT translocates to the nucleus in HCC cell lines by interacting with signal transducer and activator of transcription 1 (STAT1). This complex then suppresses FXR expression by promoting histone deacetylase 3 (HDAC3) binding to the FXR promoter [89]. A recent study found that the FXR agonist Vonafexor enhances cytotoxicity via the cGAS-STINGNF-κB signaling pathway by downregulating hepatitis B e antigen-mediated mitochondrial ROS suppression. Additionally, Vonafexor blocks nuclear translocation of c-Rel in myeloid-derived suppressor cells (MDSCs), reducing their infiltration [90]. The FXR agonist GW4064 synergizes with anti-PD-1 antibodies (Ab) to inhibit HCC growth in tumor models. Norcholic acid promotes HCC progression and immune evasion by suppressing FXR signaling, indicating that combined FXR agonist/anti-PD-1 Ab therapy is superior to immune checkpoint inhibitor monotherapy for combating HCC [91].

4.2.4. Verification of Notch1-mediated cross-regulation

Notch1 has been established as an oncogene and a biomarker of symmetric cell division [92,93]. In hepatocellular carcinoma (HCC) models using FXR knockout (FXR-KO) mice, Notch1 activation levels are significantly elevated in hepatocytes. Moreover, in the context of precancerous lesions induced by chronic liver injury, FXR expression exhibits a significant negative correlation with Notch1 levels, suggesting that under physiological conditions, FXR exerts anti-cancer effects by negatively regulating the Notch1 pathway. Conversely, downregulation or functional loss of FXR represents a key mechanism driving HCC progression [94].

Previous studies have identified aberrant upregulation of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) signaling axis as a core mechanism by which inflammation promotes liver carcinogenesis [95]. A study on non-alcoholic steatohepatitis-related HCC (NASH-HCC) demonstrated that the FXR agonist obeticholic acid (OCA) significantly suppresses the initiation and progression of NASH-dependent HCC by targeting and activating FXR, thereby upregulating SOCS3 expression and interfering with the SOCS3/Jak2/STAT3 signaling pathway [96].

It should be noted that the regulatory effect of FXR on HCC is strictly dependent on the pathological stage and cellular context. In normal hepatocytes and during the precancerous stage of chronic hepatitis–hepatic fibrosis, FXR primarily exerts its anti-cancer effects by maintaining bile acid homeostasis and inhibiting inflammation and oncogenic pathway activation. Downregulation or functional loss of FXR significantly accelerates HCC progression. However, in stromal tumor cells of advanced HCC, FXR activation may exhibit pro-metastatic potential by enhancing TGF-β-induced epithelial–mesenchymal transition (EMT). Given the core anti-cancer role of FXR in the precancerous stage and its positive regulatory effect on the HCC immune microenvironment, FXR agonists hold clear application value in primary prevention and adjuvant therapy following radical surgery for HCC. Combined treatment with FXR agonists and immune checkpoint inhibitors, such as anti-PD-1 antibodies, can overcome immune escape mechanisms partially mediated by FXR-related pathways, resulting in superior anti-HCC efficacy compared to immunotherapy alone. This finding does not contradict the core concept that “functional loss of FXR promotes HCC progression”; rather, it further validates the clinical translational value of targeting and modulating the FXR signaling pathway.

4.3. Bidirectional regulatory function of FXR

As a member of the nuclear receptor superfamily, FXR does not exclusively exert hepatoprotective effects but exhibits bidirectional regulatory functions in hepatocellular carcinoma (HCC) depending on disease stage and cellular microenvironment. FXR can mediate protective anti-cancer effects while also exerting pro-tumorigenic actions under specific conditions. This functional duality has become a core bottleneck in the translational application of FXR-targeted therapies. The previous section focused on anti-HCC mechanisms of FXR; this section primarily describes its pro-tumorigenic aspects.

4.3.1. Potential pro-tumorigenic effects of FXR in HCC

FXR promotes HCC progression by enhancing tumor cell invasion and metastasis. Existing evidence shows that FXR activation amplifies TGF-β-induced epithelial–mesenchymal transition (EMT) via the TGF-β/SMAD2/3 pathway, upregulating mesenchymal markers (N-cadherin, vimentin) and downregulating E-cadherin, thereby enhancing HCC cell invasion and migration [74]. Conversely, FXR antagonists inhibit EMT and block metastasis [75]. Under specific genetic backgrounds, FXR also exerts pro-cancer effects. In HBV-related HCC, C-terminally truncated HBx C40 mediates FXR functional loss, leading to bile acid accumulation and glucose metabolic disorders, synergistically promoting HCC progression [64]. Moreover, norcanolic acid (NorCA)-mediated negative regulation of FXR signaling further exacerbates HCC cell proliferation, invasion, and migration while promoting tumor immune escape [39].

4.3.2. Core determinants of FXR bidirectional regulatory function

The bidirectional function of FXR is governed by multiple factors. First, cell type: in normal hepatocytes, FXR activation regulates bile acid homeostasis to exert protective effects [91,92]; in mesenchymal HCC cells, it predominantly regulates EMT-related pathways to promote metastasis. Second, the tumor microenvironment and genetic background: hypoxia/inflammation-rich microenvironments, along with genetic alterations (e.g., p53 mutations, RAS activation, HBx integration), remodel FXR chromatin binding sites via epigenetic modifications, converting FXR from an anti-cancer to a pro-cancer transcription factor [64].

The tumor recurrence risk associated with FXR agonists is highly dependent on administration timing, tumor stage, and combination therapy. In precancerous stages or after radical resection, FXR agonists reduce HCC risk by ameliorating liver inflammation and fibrosis and inhibiting cancer stem cell tumorigenicity [90,97]. However, in advanced HCC or minimal residual disease, long-term FXR agonist monotherapy may potentially promote recurrence. Several reviews note that FXR agonist monotherapy has limited efficacy, and FXR function varies across tumor types and stages, warranting careful safety and efficacy evaluation [85,92,93]. Combining FXR agonists with immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) synergistically inhibits HCC growth, whereas monotherapy shows poor efficacy, suggesting that in established tumors or minimal residual disease, long-term monotherapy may fail to curb progression and could indirectly increase recurrence risk via compensatory pathway activation [91]. In summary, although existing evidence does not directly confirm that long-term FXR agonist monotherapy necessarily promotes recurrence, this risk cannot be ignored at specific stages (advanced disease, minimal residual disease). Clinical practice requires strict patient selection and prioritization of combination strategies.

4.4. Novel strategies for targeting FXR in HCC treatment

Recent studies indicate that farnesoid X receptor (FXR) holds potential as a diagnostic biomarker in HCC. A splice variant, FXRαse5, fails to activate downstream transcription in HCC cells, affecting energy metabolism and potentially linking to loss of FXR anti-cancer function [98]. Salama's team further demonstrated that combined detection of FXR and glypican 3 (GPC3) effectively distinguishes HCC from non-tumor liver lesions, with significantly better diagnostic specificity than either biomarker alone [99].

Regarding therapeutic mechanisms, celastrol inhibits FXR–RXRα interaction in hepatocytes by modulating gut microbiota and hepatic bile acid metabolism, inducing cell cycle G0/G1 arrest via the mTOR/S6K1 pathway, and ultimately suppressing HCC proliferation [100]. Dihydroartemisinin upregulates FXR expression and reduces Yes-associated protein 1 (YAP1) levels, thereby inhibiting HCC progression via bile acid metabolism regulation [101].

Notably, FXR exhibits bidirectional regulatory functions in HCC, determined by cell type, genetic background, and tumor microenvironment. In mesenchymal advanced HCC cells and hypoxia/inflammation-rich microenvironments, FXR activates the TGF-β/SMAD2/3 pathway to promote EMT and HCC cell proliferation, invasion, and migration. Under physiological conditions, FXR is a core regulator of hepatic metabolism and homeostasis, and its signaling deficiency drives HCC progression. Norcaffeic acid (NorCA) negatively regulates FXR, disrupting bile acid homeostasis, inflammation inhibition, and immune surveillance, leading to downregulation of FXR tumor suppressor signaling. This exacerbates malignant phenotypes and induces a tumor immunosuppressive microenvironment, enhancing immune evasion. These mechanisms suggest that FXR agonists can counteract NorCA-mediated inhibition by activating FXR, restoring metabolic homeostasis and reshaping the immune microenvironment to reverse immune evasion. Accordingly, combination with anti-PD-1 antibodies yields superior anti-HCC efficacy compared to immune checkpoint inhibitor monotherapy [91].

Additionally, microRNAs (miRNAs) mediate post-transcriptional regulation by targeting the 3′ untranslated region (3′ UTR) of genes, playing dual pro- or anti-cancer roles in HCC [[102], [103], [104]] and exhibiting close bidirectional regulatory interactions with the FXR pathway. On one hand, miRNAs can directly target the FXR 3′ UTR to regulate its expression or indirectly interfere with FXR transcriptional activity, mediating abnormalities in bile acid homeostasis, metabolic reprogramming, and tumor-related pathways [89]. On the other hand, FXR, as a nuclear transcription factor, can directly bind to miRNA promoters to regulate their transcription, amplifying effects on the HCC malignant phenotype via cascades [79]. Targeting the miRNA–FXR regulatory axis may provide a novel direction for precision intervention in HCC and holds clinical translational value when combined with FXR modulators.

The specific mechanisms of FXR action in HCC are summarized in Table 3.

Table 3.

Mechanisms of action and therapeutic strategies of FXR in HCC.

Category	Core mechanism	Key pathways/factors	Functional effects/clinical implications	References
Metabolic homeostasis regulation	Glucose metabolism reprogramming: inhibits gluconeogenic rate-limiting enzymes under physiological conditions; suppresses key glycolytic enzymes in tumor cells	PEPCK, G6Pase; SHP/FOXO1/HNF4α axis; HK2, GAPDH, LDHA; IL-6, TNF-α	Quercetin exerts anti-cancer effects via this pathway; FXR downregulation + HBx C40 synergistically promote glycolytic reprogramming in HBV-HCC	[16,64,[67], [68], [69]]
	TDG deficiency leads to FXR/SHP axis dysregulation, BA accumulation and glucose metabolism disorders	TDG/SHP axis, bile acids (BA)	BA overload is a pathogenic factor for HCC; FXR deficiency drives hepatocarcinogenesis	[[70], [71], [72]]
	FXR inactivation induces gut dysbiosis and metabolic disorders	Gut microbiota, MASH-related pathways	Links the intestinal microenvironment to HCC development	[63,78]
	BSEP deficiency leads to BA accumulation and antagonizes FXR activity	ABCB11/BSEP, antagonistic BA	Induces cholestatic liver injury and promotes liver tumor formation	[73]
	FXR induces FGF15 secretion and activates hepatic Hippo signaling	FGF15–Hippo pathway	Suppresses BA metabolism and excessive liver proliferation, blocks HCC initiation	[74]
Tumor signaling pathway regulation	Upregulates SOCS3, inhibits STAT3 phosphorylation	SOCS3/STAT3, liver cancer stem cells (CSCs)	Targets and inhibits CSCs, reduces tumorigenicity	[77,78]
	Inhibits FXR/SHP pathway, amplifies p53 pro-apoptotic positive feedback loop	T-β-MCA/p53, miR-34a/SIRT1	Enhances tumor cell apoptosis, exerts anti-cancer effects	[79]
	FXR activation enhances TGF-β-induced EMT; antagonists inhibit this process	TGF-β/SMAD2/3, EMT-related markers	FXR antagonists are candidate EMT-inhibitory drugs	[80,81]
	Upregulates FXR, downregulates β-catenin and downstream target genes	FXR/Wnt/β-catenin, cyclin D1	α-Linolenic acid inhibits HCC proliferation via this pathway	[83]
	Silencing ACSL4 upregulates FXR, reduces BA, and impedes M2 polarization	ACSL4/M2 macrophages, BA	Modulates tumor-associated macrophages, improves HBV-HCC microenvironment	[84,86]
	TKT–STAT1 complex binds to FXR promoter and inhibits its expression	TKT/STAT1/HDAC3, FXR promoter	Metabolic enzyme epigenetically regulates FXR, promoting HCC progression	[89]
	Inhibits mitochondrial ROS, activates cGAS–STING–NF-κB axis	cGAS–STING/NF-κB, MDSCs	Enhances immune cytotoxicity, reduces MDSCs infiltration, boosts anti-tumor immunity	[90]
	FXR agonist combined with anti-PD-1 antibody suppresses immune evasion	PD-1 immune checkpoint, NorCA	Combination therapy shows significantly better anti-tumor efficacy than monotherapy	[90,91]
	FXR negatively regulates Notch1 pathway, inhibiting its oncogenic role	FXR/Notch1, precancerous pathway	FXR deficiency leads to Notch1 hyperactivation, accelerating HCC development	[92,94]
	Upregulates SOCS3, interferes with Jak2/STAT3 inflammatory oncogenic axis	SOCS3/Jak2/STAT3, NASH-HCC	OCA inhibits NASH-dependent HCC progression via this pathway	[95,96]
Targeted diagnosis and therapy	Low FXR expression combined with GPC3 detection to differentiate lesion types	FXR/GPC3, HCC vs. non-tumor liver disease	Improves HCC diagnostic specificity, represents a potential diagnostic biomarker	[98,99]
	Inhibits FXR–RXRα interaction, induces cell cycle G0/G1 arrest	FXR–RXRα, mTOR/S6K1	Celastrol inhibits HCC proliferation via this pathway	[100]
	Upregulates FXR, reduces YAP1, regulates bile acid metabolism	FXR/YAP1, BA metabolic pathway	Dihydroartemisinin targets this pathway to inhibit HCC progression	[101]
	FXR exerts bidirectional regulatory effects depending on cell type/microenvironment	FXR, TGF-β/SMAD2/3, immune microenvironment	Anti-cancer in normal/precancerous stages; promotes tumor invasion/metastasis in advanced stages	[64,81,91]
	Bidirectional regulation between miRNA and FXR, mediating post-transcriptional modification	miRNA–FXR axis, gene 3′-UTR	miRNA targets FXR; represents a novel target for precision intervention in HCC	[[102], [103], [104]]

5. Conclusions and Prospects

Farnesoid X receptor (FXR) serves as a central regulatory hub throughout the entire disease continuum from hepatic inflammation and fibrosis to hepatocellular carcinoma (HCC). It represents a critical molecular node that integrates metabolic homeostasis imbalance, chronic inflammatory cascade amplification, fibrotic tissue remodeling, and malignant transformation of hepatocytes. Under physiological conditions and in the early stages of liver disease, FXR maintains bile acid metabolism via the gut–liver axis, thereby blocking the initiation of inflammation at its source. Simultaneously, it suppresses core inflammatory pathways such as TLR4/NF-κB and the NLRP3 inflammasome, curbs aberrant activation of hepatic stellate cells and extracellular matrix deposition, and disrupts the vicious “inflammation–fibrosis” cycle, acting as a key protective factor in liver homeostasis. Conversely, FXR dysfunction or epigenetically mediated signaling inactivation leads to bile acid accumulation, metabolic reprogramming, and sustained activation of oncogenic pathways, thereby becoming a major driver of HCC initiation and progression. Functional activation of FXR effectively inhibits HCC cell proliferation and invasion, remodels the tumor immune microenvironment, and blocks immune evasion. The bidirectional regulatory effects of FXR exhibit strict dependence on cellular context, disease stage, and tumor microenvironment, which is not only a core feature of its biological function but also a key bottleneck in targeted therapy.

In this review, the vast majority of existing evidence is derived from in vitro cell experiments and animal models, with a marked paucity of large-sample, multicenter, high-quality clinical studies on FXR modulators in patients with chronic liver disease and HCC. Current clinical explorations generally suffer from limitations such as small sample sizes, insufficient follow-up duration, limited efficacy of monotherapy, and inadequate long-term safety data. These challenges not only hinder the comprehensive support for the standardized clinical application of FXR-targeted drugs but also constitute a critical gap restricting the translation of fundamental research into clinical practice.

Future research should prioritize filling these clinical evidence gaps, focusing on the core challenges of clinical translation of FXR-targeted therapies. Large-sample, multicenter, randomized, double-blind, placebo-controlled clinical trials are urgently needed to systematically evaluate the safety, efficacy, and long-term prognostic impact of different FXR modulators across various stages of chronic liver disease and distinct HCC treatment scenarios, thereby clarifying the optimal dosage, treatment timing, suitable patient populations, and combination regimens. Concurrently, long-term clinical data should be accumulated through real-world studies to address issues such as the limited efficacy of existing monotherapy and unclear potential medication risks. On this basis, further application of multi-omics technologies is warranted to dissect the tissue-specific functional differences and the molecular switch mechanisms underlying the bidirectional regulation of FXR in the liver and intestine. The development of novel FXR modulators with high selectivity and tissue targeting, the identification of biomarkers predictive of clinical treatment response, the establishment of a molecular classification and precision diagnosis/treatment system for liver diseases based on FXR signaling status, and the construction of an FXR-targeted integrated prevention and treatment strategy covering the entire course of liver diseases are all essential steps. Ultimately, these efforts will facilitate the leap of innovative FXR-targeted therapies from basic research to clinical application, providing patients with chronic liver disease and HCC with novel treatment options supported by robust evidence-based medicine.

CRediT authorship contribution statement

Cheng Qiuluo: Writing – original draft. Huang Guiqun: Investigation. Han Xue: Investigation. Zhu Ying: Writing – review & editing.

Declarations

All data summarized in this review are extracted from publicly available published studies. This manuscript has not been submitted to any other journal for publication. All authors have read and approved the final version of the manuscript. No human participants or animal experiments were performed in this review, so relevant ethical approval is not required.

Declaration of competing interest

The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was supported by the National Natural Science Foundation of China (Grant No. 82274260). The funding source had no role in the study design, data collection, analysis, interpretation, writing of the manuscript, or decision to submit the article for publication.

Data availability

The data that has been used is confidential.