The nuclear receptor superfamily is categorized into two classes based on DNA-binding properties: One class function as homodimers, while another class forms heterodimers with RXR for DNA interaction (4). FXR belongs to the latter class and shares structural homology with other members, including the retinoic acid receptor, the thyroid hormone receptor and the vitamin D₃ receptor (4). The structure of nuclear receptors typically encompasses five domains: The amino terminal transcriptional activation function-1, a DNA binding domain, a hinge region, a ligand binding domain (LBD) and the carboxyl terminal activation function-2 (AF-2). This architecture facilitates RXR-mediated heterodimerization, as illustrated in Fig. 1A-C (1,8). FXR is originally cloned from rats using degenerate primers corresponding to the semi-conserved DNA-binding domain of the nuclear receptor (4). Early functional characterization reveals weak farnesol-induced activation; however, the absence of endogenous ligands under physiological conditions initially classified FXR as an orphan nuclear receptor. A paradigm shift occurred in 1999 when endogenous BAs were demonstrated to robustly activate FXR at physiological concentrations, triggering downstream transcriptional responses. This discovery propels extensive investigations into FXR's regulatory roles in BA homeostasis and hepato-enteric pathophysiology. Structurally, FXR's LBD mirrors the characteristic three-layered helical sandwich observed across nuclear receptors, which was resolved in 2003 (Fig. 1C) (9,10). Of particular functional significance is, H12, which harbors AF-2 and establishes hydrophobic interactions with H3 and H4, stabilizing co-activator binding through LXXLL motif engagement at the LBD interface (9,10). In contrast to most ligands, BAs occupy the FXR LBD binding site in an opposite direction, and there are two sites binding to the LXXLL motif simultaneously. This distinctive orientation enhances binding affinity compared with single-motif co-activators. Comprehensive structural analyses of FXR have been systematically documented in prior crystallographic studies (11,12).

Two FXR genes have been identified: FXRα and FXRβ. In rodents, rabbits and dogs, FXRβ has been shown to be activated by lanosterol, while in humans and primates, it constitutes a non-functional pseudogene (13). Human physiology specifically expresses four functional FXRα isoforms (FXRα1-4) differentiated by their amino-terminal domains, as illustrated in Fig. 1D (14). This is due to differential promoter usage and alternative exon splicing patterns. A four-amino acid residue insertion MYTG in the hinge region leads to the difference between FXRα1/α3 and α2/α4, which potentially impacts receptor functionality. In addition, tissue- and species-specific expression profiles are observed in these isomers. Murine models demonstrate predominant hepatic and intestinal co-expression of both FXR subtypes, whereas renal tissue preferentially expresses FXRβ and adrenal glands favor FXRα (15). Human expression patterns similarly mirror this compartmentalization, with hepatocytes predominantly expressing FXRα1/α2 isoforms, while enterocytes show preferential FXRα3/α4 expression (16). Furthermore, there is also evidence that dynamic regulation of FXR isoform expression is closely associated with the metabolic progress and physiological states (17-19).

Genetic polymorphisms in nuclear receptor superfamily members (vitamin D receptor, peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), small heterodimer partner (SHP), hepatocyte nuclear factor-1-α and hepatocyte nuclear factor-4α (HNF4α) establish disease predisposition through phenotypic modulation (20-27). Clinical investigations implicate FXR genetic variation in hepatobiliary pathologies, exemplified by four novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) identified in intrahepatic cholestasis of pregnancy (28). The amino terminus contains two ATG parts (M1 and M5), which could be identified as translational initiation site. M1 plays the initiation role in humans, in addition, -1g>t and M1V mutations impair protein expression and reduce transcriptional activation of ileal BA binding protein (IBABP)/bile salt export pump (BSEP) promoters, suggesting compromised translational efficiency. M173T similarly affects IBABP and BSEP promoter activation.

A study on FXR polymorphism in different races conducted by Marzolini et al (20) found several meaningful single nucleotide polymorphisms compared with an FXR reference sequence from GenBank, including G-1T, C643T (H215Y) and G646T (A216S). Furthermore, two synonymous polymorphisms (C783T, 261N; 1341T, 447H) are included in the aforementioned study as well, whose locations predict amino acid differences within the hinge region of FXR. The expression of SHP and organic anion transporting polypeptide, two FXR target genes, was significantly decreased in liver carrying FXR (G-1T) compared with FXR (-1G). However, BSEP, another FXR target gene, is unassociated with an FXR polymorphism. This differential regulation suggests target gene-specific modulation mechanisms by FXR genetic variants, highlighting the complexity of receptor-target gene interactions.

As reviewed, FXR shares its structural homology with classical nuclear receptors in its ability to form heterodimers with RXR, subsequently binding DNA to transcriptionally activate downstream target genes. The cognate DNA recognition, initially characterized as FXRE, is subsequently designated the BA response element, due to its activation by endogenous BA ligands (4). The canonical FXRE configuration comprises a conserved (AGGTCA) hexamer arranged as an inverted repeat with single nucleotide spacing (IR1) (29), representing both the most prevalent and highest affinity DNA binding configuration for nuclear receptor dimers (29,30). In addition, there are other FXRE, such as IR0, IR8 (31), ER8 (32) and DR1 (33). Some of the FXRE sites are tissue-specific, and a study of Chip-Seq in murine treated with GW4064 showed only 11% of the sites were shared between the liver and intestine (34).

Farnesoid derivatives are intermediates of mevalonate pathway metabolism and can activate FXR at supra-physiological dose concentrations (4). BAs, the natural ligand of FXR, activate FXR at physiological concentrations. Comparative analyses revealed chenodeoxycholic acid (CDCA) as the most potent endogenous agonist, exhibiting activity superior to deoxycholic acid, lithocholic acid (LCA) and cholic acid (2). However, a mechanistic exploration of FXR's roles in sterol homeostasis has been constrained by available pharmacological tools. While CDCA serves as the archetypal endogenous ligand, its extensive interactions with BA chaperone proteins, metabolism into LCA and non-specific cellular effects render it suboptimal for experimental applications. These limitations motivated the development of GW4064, a synthetically optimized FXR agonist demonstrating superior specificity and pharmacological stability (2). Of note, multiple FXR-targeted therapeutics have advanced through clinical development pipelines for cholestatic and metabolic disorders including primary biliary cholangitis, primary sclerosing cholangitis and non-alcoholic steatohepatitis (NASH) (Table I). Paralleling agonist development, novel modulatory agents exhibiting distinct activation profiles relative to CDCA and GW4064 are emerging, with comparative pharmacodynamic characteristics outlined in Table II.

The regulation of FXR in vivo is complex, and its physiological effects include several categories: i) It maintains BA pool homeostasis, and reduces BA concentration in the liver by increasing BA output and reducing BA synthesis; ii) it reduces blood lipid levels and regulates plasma lipoproteins; iii) it exerts liver protection and regeneration; iv) it regulates glucose metabolism and gluconeogenesis (35); v) it regulates blood vessel clotting and anticoagulation molecules (36,37); and vi) it is involved in urine volume regulation and anti-renal fibrosis (38,39).

FA homeostasis is governed by a balance between uptake and elimination, with disruptions in this equilibrium contributing to metabolic pathogenesis. In this section, the regulatory roles of FXR in FA transport, de novo synthesis and catabolism were systematically evaluated (Fig. 2).

Cellular FA internalization is mediated by specialized transporters, notably CD36, caveolins (CAVs) and the FA transport protein (FATP) family (40).

CD36 (SR-B2/FAT) is a membrane-spanning glycoprotein facilitating absorption of long-chain FAs and oxidized low-density lipoprotein (LDL) uptake (40). A mechanistic study demonstrated that hepatic CD36 overexpression exacerbates FA influx in NAFLD murine models, whereas its genetic silencing alleviates steatosis-associated lipid deposition (41). As a transcriptional target of PPARs and other nuclear receptors (40), CD36 expression has been shown to be modulated by pregnane X receptor-mediated transcriptional activation, driving hepatic triglyceride (TG) accumulation through enhanced lipid uptake (42). Small heterodimer partner is an atypical nuclear receptor that lacks DNA-binding domain, which is regarded as the target gene of FXR. GW4064 dose-dependently suppresses CD36 effectively reversing hepatic steatosis in diet-induced obese mice (43). Complementary evidence from diosgenin mechanistic studies confirms FXR/SHP-mediated CD36 downregulation as an anti-steatotic pathway (44). These findings collectively established FXR/SHP/CD36 as a pivotal regulatory node in FA homeostasis.

CAVs are essential components of caveolae (one site of endocytosis) involved in several biological functional processes, such as vesicle formation and lipid droplet formation. CAV-1 has been extensively investigated in prior studies. Preclinical investigations have revealed CAV-1 upregulation within mitochondrial inner membranes and lipid droplets of choline deficiency-induced fatty liver models (45), while CAV-1 knockout mice have been shown to exhibit attenuated hepatic lipid storage capacity (46), implicating its necessity for physiological lipid storage. Further characterization of CAV-1(−/−) mice reveals compromised PPARα signaling, manifested by downregulated carnitine palmitoyl-transferase (CPT) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These perturbations were found to be correlated with mitochondrial dysfunction and to impair FA β-oxidation (47). In summary, CAV-1 deficiency concurrently disrupts FXR signaling and BA metabolism, suggesting its dual regulatory role-modulating both anabolic and catabolic pathways-analogous to multifaceted functions of CD36.

The FATP family represents another critical determinant of transmembrane FA flux. Motojima et al (48) reported FATP is upregulated in the liver of mice threated with the PPAR activator Wy14643. FATP-mediated lipid metabolic reprogramming has been extensively characterized in oncogenesis (49). FATP2 displays hepatorenal expression, whereas FATP5 exhibits liver-specific localization (50). A previous study on knockout FATP2 or FATP5 mice found that FA uptake was reduced and hepatic steatosis was reversed (51). Interestingly, when PPARα agonist was administered to ApoE (−/−) FXR (−/−) mice, Lee et al (52) observed that despite lipid reduction which resulted in NAFLD and atherosclerosis alleviated, the expression of FATP1 and CD36 was upregulated. This suggests that FATP family members may not simply promote lipid accumulation, but enhance lipid transport to drive intracellular lipid metabolism pathways.

FXR inhibits the de novo synthesis of FAs. During the de novo synthesis of FAs in the body, acetyl-CoA carboxylase (ACC) can carboxylate acetyl CoA to form malonyl CoA, which is a rate-limiting enzymatic step in this pathway. Experimental evidence demonstrates ACC's pivotal metabolic role. ACC (−/−) mice have a lower weight than the wild-type (WT) group, and using ACC inhibitors to treat mice induced by diet could upregulate FA oxidation (FAO) and inhibit FA synthesis, thus leading to NAFLD relief (53). In addition, sterol regulatory element binding protein 1 (SREBP-1) and carbohydrate reaction element binding protein (ChREBP) are also essential transcriptional regulators in the lipid synthesis pathway. In an ob/ob mouse model of obesity and insulin resistance, the expression of SREBP-1 and ChREBP were significantly increased, and the dual or selective inhibition of these factors effectively alleviated the liver steatosis of the model mice (54,55).

In FXR deficient mice, SREBP-1, FA synthase (FASN) and stearoyl-CoA desaturase-1 were significantly upregulated, indicating that FXR might inhibit the synthesis of FA to improve liver steatosis (56). On the contrary, CA administration significantly downregulated SREBP-1 and its transcriptional targets, while impairing lipogenic capacity in murine hepatocytes (57). As one of the key target genes of FXR, the role of SHP has been investigated. Mechanistic investigations have revealed that SHP mediated SREBP-1c promoter regulation. CDCA-induced SHP upregulation has been shown to be inversely correlated with SREBP-1c target gene suppression. CA or GW4064 could attenuate serum TGs along with sterol regulatory element-binding protein 1 (SREBP1) decreases in SHP (+/+) mice; however, this was absent in SHP (−/−) mice, establishing the FXR/SHP axis as a dual regulator of FA transport and lipogenesis through SREBP-1c modulation.

ChREBP has been shown to regulate glucose-induced fat production. Under hyperglycemic conditions, ChREBP combines with Max-like protein and ChREBP to form two box-like motifs, therefore promoting the expression of its target genes, such as liver-type pyruvate kinase (LPK), FASN and ACC1, driving enhanced FA and TG biosynthesis (58). Given that FXR is negatively associated with the expression of LPK, FASN and ACC, Caron et al (59) hypothesized that FXR interfered with the transcriptional activity of ChREBP. Fasting-refeeding studies revealed that INT-747, a synthetic FXR agonist, significantly attenuated high-carbohydrate-induced increase in mRNA expression of LPK in WT mice, with parallel observations in IHH and HepaRG human hepatocytes. FXR did not affect ChREBP nuclear translocation, but decreased transcription coactivator binding to L4L3 region of LPK promoter to release ChREBP, meanwhile inducing the recruitment of silencing mediator of retinoid and thyroid hormone receptor (a transcriptional corepressor) leading to a prevention of the FXR-dependent repression of LPK at a high glucose concentration. This mechanism could be extended to other ChREBP target genes under hyperglycemic conditions, collectively reducing the generation of acetyl-CoA, suppressing de novo lipogenesis, and potentially ameliorating NAFLD pathogenesis.

In addition, due to the enterohepatic cycle of BA metabolism, the fibroblast growth factor (FGF) family members have also been extensively investigated. The expression and excretion of fibroblast growth factor-15/19 are induced by FXR in the intestine. The intestinal activation of FXR stimulates the secretion of FGF-19, which negatively regulates cholesterol 7α hydroxylase (CYP7A1) transcription after binding to FGF4/klothoβ (60). FGF-19 inhibits insulin-induced FA synthesis by i) decreasing the activity of SREBP-1c; ii) enhancing STAT3 signaling and iii) downregulating PGC1β. Furthermore, the FGF19/SHP/SREBP-1c axis suppresses lipogenic enzyme expression while promoting FAO through ACC2 downregulation (61).

In FA metabolism, FA from acetyl-CoA and malonyl-CoA, and FFA from TGs are catalyzed by fatty acyl-CoA synthetase to form fatty acyl-CoA, which is the main step in FA β-oxidation. Products are then transferred into the mitochondria by carnitine CPT1a for the subsequent step. Accumulating evidence demonstrates FXR's regulatory role in facilitating this metabolic cascade.

Previous research on FXR-mediated FA transport has revealed functional interplay with PPARα. The PPAR family is part of the nuclear receptor sup-family, including PPAR-α, PPAR-β/δ and PPAR-γ. PPARs serve as primary regulators of glucose and lipid homeostasis, establishing them as therapeutic targets for metabolic disorders and oncogenesis. Experimental evidence indicates that PPARα-deficient mice develop pronounced hepatic steatosis (62), while FXR (−/−) ob/ob mice exhibit significant PPARα downregulation (63). These observations suggest the potential FXR-mediated regulation of FA β-oxidation through PPARα-dependent mechanisms. Substantiating this hypothesis, Pineda Torra et al (64) found that the incubation of a human HepG2 cell line with CDCA or GW4064 led to a significant induction of PPARα in a transcriptional level. Through mutation analysis, they found αFXRE in the human PPARα promoter. In addition, induction of human PPARα by CDCA enhanced the expression of PPARα target gene CPT1, which was not observed in mice. This indicated that the underlying mechanism might be species-specific, which is worth investigating further. In addition, FXR could activate the transcription of liver carboxylesterase 1, which enhanced FA β-oxidation through PPARα (65). While reviewing the previous article, it was also found that the FXR/SHP axis may induce the AMPK-ACC-CPT1α mechanism to promote FA β-oxidation (66).

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) contributes to the regulation of certain transcription factors, such as PPARα and -γ as the coactivator, thus modulating several genes in metabolic pathways (67). In a study on the pharmacological effect and mechanism of Nuciferine, it was found that Nuciferine could attenuate hepatic steatosis in HFD/STZ-induced diabetic mice through the PPARα/PGC1α pathway (68). In addition, FXR is activated by PGC1α, which promotes PGC1α-mediated FA oxidation (69). In conclusion, FXR tended to promote FA β-oxidation in the majority of studies.

Cholesterol undergoes hepatic biosynthesis with subsequent conversion to BAs; this constitutes its principal metabolic fate. BAs are divided into free BAs and conjugated acids in structure, or primary BAs and secondary BAs in source. Given the established role of FXR in regulating BA homeostasis, this section focuses on its contribution to cholesterol metabolite dynamics and enterohepatic BA cycling (Fig. 3).

Cholesterols could be catalyzed by CYP7A1 into 7α hydroxycholesterol, then undergo a series of complicated enzymatic reactions, finally being transformed into primary free BAs, such as CA and CDCA, or combined with the corresponding glycine or taurine to produce primary conjugated acids to discharge into the intestine. CYP7A1 functions as the key enzyme of the classic BA synthesis pathway (70). 12α-hydroxylase (CYP8B1) determines the ratio of CA and CDCA.

SHP, the target gene of FXR, can inhibit the expression of CYP7A1 by blocking the trans-activation of the liver activator liver receptor homolog-1 (LRH-1) and HNF4α (71,72). In addition, FXR can also reduce BA synthesis by inhibiting CYP8B1, and the mechanism is similar (70,73).

Following synthesis and conjugation with glycine or taurine, BAs are secreted into bile canaliculi through BSEP, and then enter the gallbladder for storage. Nutrient-responsive gallbladder contraction initiates bile release into the duodenal lumen. In the distal small intestine, BAs are reabsorbed into the blood through apical sodium-dependent BA transporter. Next, in intestinal epithelial cells, they are reabsorbed by IBABP and organic solute transporter alpha/beta (OSTα/β) into portal circulation. Hepatocyte reuptake completes this enterohepatic cycling mechanism that is essential for maintaining BA pool homeostasis. Almost all of these transporters involved in the enterohepatic circulation of BAs are regulated by FXR (74,75). Others include multidrug-resistant associated protein 2 (MRP2) (76), and multidrug-resistant P-glycoprotein 3 (77), which promote hepatic BA outflow.

Plasma lipoprotein is the blood component that transports plasma lipids. It was reviewed independently to elucidate the link between FXR and blood lipid (Fig. 4). This part actually has a crosstalk with the FA metabolism and cholesterol metabolism. Very low-density lipoprotein (VLDL), synthesized primarily in hepatocytes, mediates the hepatic export of TG and cholesterol to peripheral tissues. Upon entering circulation, nascent VLDL acquires apolipoprotein C (apoC) from high-density lipoprotein (HDL), where apoC-II activates endothelial lipoprotein lipase (LPL) to hydrolyze VLDL-associated TG. Through progressive lipid exchange with HDL, VLDL undergoes remodeling into cholesterol-enriched LDL, with circulating VLDL and LDL levels serving as established clinical biomarkers for the evaluation of dyslipidemia.

Clinical investigations indicated that pharmacologic FXR activation significantly reduces serum TGs, while aggravating liver cholesterol accumulation and atherogenic serum lipoprotein profiles (high LDL level) in FXR-deficient models (6,78). Consistently, CDCA was found to be associated with decreased serum TG and VLDL production in patients with hyperlipidemia, while colestyramine (BA chelating agent) exhibited the opposite trends (79). The antilipidemic action of CDCA involves multiple regulatory axes. One is the FXR/SHP/HNF4α axis (80). Hirokane et al (80) found that, following the treatment of HepG2 cells with CDCA, the expression of microsomal TG transfer protein (MTP) and apoB are attenuated as HNF-4 is suppressed by SHP. Similarly, FXR/SHP/HNF4α can also reduce VLDL by partially inhibiting the expression of phospholipase A2 group XIIB, a mediator of VLDL (81). From the aforementioned studies, the role of apoC II and LPL were reported. The former activates LPL, and then the latter hydrolyzes TG, leading to TGs clearing. ApoC III is also a component of various lipoproteins, which is known as the inhibitor of LPL, meanwhile affecting hepatic lipase, therefore impairing the conversion of VLDL to IDL and LDL (82). FXR can promote TG clearing by inducing hepatic apoC-II and inhibiting apoC-III and angiopoietin-like protein 3 (83,84). CDCA could lead to FXR combined promoter of apoC-II, but this does not exist in FXR-deficient mice.

HDL is mainly synthesized in the liver and partly in the small intestine, which is responsible for reverse cholesterol transport-the process of shuttling peripheral cholesterol to hepatic tissues for biliary excretion or direct intestinal elimination. Lipid transfer proteins, particularly phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP), govern lipoprotein remodeling through phospholipid and cholesterol exchange between VLDL and HDL particles. FXR activation by CDCA elevates PLTP activity and induces CETP expression through ApoE-mediated pathways (85,86), thereby modulating lipoprotein redistribution. Scavenger receptor class B type I (SRBI), a key HDL receptor parallel to CD36 in lipid metabolism, demonstrates FXR-dependent upregulation in murine with CA-containing diet, whereas FXR deficiency abrogates this dietary response, establishing SRBI as a regulatory node in FXR-mediated HDL homeostasis.

FAs, cholesterol and plasma lipoproteins are inextricably linked and convert each other, leading to the crosstalk between metabolic mechanisms, which enables a more comprehensive study of the role of FXR in lipid metabolism and BA circulation.

Due to its role in BA circulation and gut microbiota, the development of intestinal tumors involves a complex interaction with the FXR's expression and activity. Beyond the direct regulation of BA synthesis/transport machinery, FXR-mediated pathological mechanisms extend to bidirectional crosstalk with microbial communities and immunomodulatory pathways.

The gut microbes have profound effects on BA metabolism by promoting the decoupling, dehydrogenation and dihydroxylation of primary BAs in the distal small intestine and colon, thereby increasing the chemical diversity of Bas (105). Gut microbes and FXR, as two factors in BA regulation, also interact with each other through the change of BA pool. Sayin et al (105) analyzed the differences in BAs between germ-free (GF) and conventionally raised (CONV-R) mice. The BAs' composition spectrum showed organic differences between two groups, and the BAs' pool of CONV-R was reduced by 71±2%. Further intestinal segment analysis revealed the effect of the presence of intestinal microbes on the BAs' profiles of different intestinal segments; that is, the modification of BAs by microorganisms. Given FXR's role in BA balance, they explored the activities of FXR and found that FXR, SHP and FGF15 are upregulated in distal ileum of CONV-R mice compared with the GF group. Furthermore, the upregulation of SHP, FGF15 and IBABP was eliminated when FXR^−/− mice were rederived as GF. These findings revealed that the effect of gut microbes on BAs is induced by FXR. In patients with CRC, 16s rRNA shows multiple mucosal microbes increased, including the genera Bacteroides, Curto bacterium and Campylobacter (106). In addition, these microbes have a stronger ability to produce DCA, which inhibits FXR and promotes CRC. Consistent with this, the low expression of FXR was observed in a different CRC study, meanwhile researchers found that FXR was negatively correlated with the PI3K pathway and EMT (107). By contrast, FXR deficiency results in the of BA profiles, which then affects gut PH and, ultimately, enterotoxigenic Bacteroides Fragilis (ETBF) mucosal colonization, contributing to the development of CRC (108).

Immune microenvironment alterations emerge through dual mechanisms. One reason for that is microbial imbalance. Bacteroides fragilis toxins, produced by ETBF, have a carcinogenic effect on colonic epithelial cells. It can induce mucosal Th17 response, which in turn selectively leads to the activation of the NF-κB pathway (109,110). In addition, Guo et al (108) demonstrated that BA levels affect IgA concentrations, which serve as the first line of defense for intestinal immunity. Secretory IgA is increased in the high-BA group, and decreased in the low-BA group. This change of immune environment also plays a synergistic role in the colonization of intestinal microbiota and CRC. Another reason for that was that FXR directly influences immune cell function and inflammation resolution. Colitis-associated cancer (CAC) is a subtype of CRC associated with inflammatory bowel disease (IBD). Macrophages are located in the intestinal epithelium sublaminar propria, mediating the inflammatory response to foreign substances, playing a role in defense, clearance and antigen presentation. Previous studies have shown that the occurrence of inflammation impaired BA homeostasis, and the activation of FXR exerted a protective effect on the intestine (111,112). Compared with healthy tissues, FXR and downstream gene expression was decreased in CAC tissues, while proinflammatory factors were significantly increased. These cytokines resulted in the upregulation of Paneth and goblet cell markers, promoting organoid budding and branching, which suggests that the stemness of intestinal stem cells was promoted, therefore contributing to CAC. Since it has been previously suggested that FXR reduces IL-17 and IFN, and Th17 cells secreting inflammatory cytokines have been shown to be associated with CAC mouse models, Dong et al (111) explored the effect of FXR agonist Fexaramine D on tumor progression. The results revealed that FXR activation enhanced the polarization and maturation of macrophages, which further led to the activation of Th17 cells (111). Furthermore, inflammation drove an increase in innate lymphoid cells (ILC) in IBD, particularly ILC3. The activation of FXR not only blocked the activation of IL-17a and IL-17f in ILC but also regulated the maturation and differentiation of ILC (112).

Collectively, intestinal carcinogenesis emerges from dynamic FXR-mediated crosstalk between BA metabolism, microbial ecology, barrier integrity and immune surveillance. As a primary regulator of BA homeostasis, FXR represents both biomarker and therapeutic target in CRC development, with pharmacological activation holding promise for intercepting microbiome-driven malignancy progression.

According to data from the World health Organization (http://gco.iarc.who.int), breast cancer ranks first in incidence and mortality among all cancer types in women. Estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) status constitute critical determinants of metastatic progression, with osseous metastasis being the most frequent dissemination pattern. FXR has been found to be expressed in primary breast cancers with bone metastases and plays an important role in osteo-mimetism of tumor cells to result in the osteo-tropism of breast cancer (113). Mechanistic investigations by Silva et al (114) revealed that bone-derived sodium deoxycholate enhanced the metastatic potential of MDA-MB-231 cells through FXR upregulation and nuclear translocation-an effect abrogated by Z-guggulsterone-mediated FXR inhibition (114,115). However, another study showed that FXR activators CDCA and GW4064 resulted in the apoptosis of MCF-7 and MDA-MB-468 cell lines (116). Of note, FXR's oncogenic role exhibits concentration-dependent duality. A low DCA concentration (10 µmol/l) promotes metastasis, while a high DCA (100-150 µmol/l) causes apoptosis (114). Furthermore, it has been shown that the mRNA expression of SHP, MRP2 and IBABP is induced in breast cancer lines following treatment with a low concentration of GW4060 (3 µmol/l) (116). The study by Alasmael et al (117) also supported that the activation of FXR induces apoptosis, without increasing the migration potential. Discrepancies between these studies likely reflect methodological variations in FXR activation thresholds and cellular context dependencies (117).

For ER-α-positive breast cancer, tamoxifen (tam) is the first-line endocrine therapy. However, drug resistance often occurs on account of HER2⁺. Therefore, the combination of endocrine therapy and targeted therapy is the optimal treatment for patients with HR⁺HER2⁺ breast cancer. Targeting HER2 is more critical. Giordano et al (118) found that the activation of FXR by GW4064 and CDCA inhibited the growth of a tam-resistant MCF-7 TR1 cell line. Their results demonstrated that CDCA reduced HER2 expression and impaired EGF-mediated HER2 and p42/44 MAPK phosphorylation. This suggested that the inhibition of HER2/MAPK through FXR may offer a new therapy direction for HR⁺HER2⁺ breast cancer.

Additional pathophysiological interactions emerge through leptin signaling modulation (119). GW4064 inhibits the growth, migration and invasion of breast cancer induced by leptin, affecting tumor-promoting activities of cancer-associated fibroblasts. The underlying mechanism showed that FXR increased the expression of suppressor of the cytokine signaling 3, leading to the inhibition of leptin signaling and downregulation of its target genes.

These findings suggest that targeting FXR may provide a new direction for breast cancer treatment but should take into consider the biological context and dose effects.