Primary cilia are found on nearly every vertebrate cell, and their evolutionary roots run deep. Comparative phylogenetic studies of ciliary genes reveal that the basic blueprint of this organelle has been conserved across vast stretches of life’s history, underscoring how fundamentally important it is to cellular physiology. Structurally, the primary cilium is built around a microtubule-based skeleton called the axoneme, which grows out of a modified centriole known as the basal body. Unlike the beating, motile cilia that line the airways, primary cilia are generally non-motile, and their nine pairs of microtubules are arranged in the classic 9+0 configuration rather than the 9+2 arrangement that powers movement. The entire organelle is sheathed in a specialized extension of the plasma membrane, and its interior is physically separated from the cytoplasm at the base by a selective barrier called the transition zone, which functions as a gatekeeper controlling which proteins can enter.

Building and maintaining a cilium is an energy-intensive logistical operation. The organelle contains no machinery for protein synthesis, so every component must be ferried in from the cell body along the axonemal microtubules. This transport system, called intraflagellar transport, or IFT, uses molecular motors such as KIF3AB and KIF17 to haul cargo building blocks toward the ciliary tip, while dynein motors carry return traffic back to the base. Recent work characterizing the IFT cycle has revealed how trains of these motors are coordinated, and how the number of active motors governs transport velocity under load. A multi-protein complex known as the BBSome, named for its role in Bardet-Biedl syndrome, acts as a cargo adaptor that exports specific signalling proteins from the cilium, adding another layer of control. Disrupting any element of this delivery network can compromise the organelle’s composition and, by extension, its ability to relay signals.

The review emphasizes that cholangiocyte primary cilia are exquisitely positioned to monitor the biliary microenvironment, projecting directly into the lumen of the bile duct. Seminal experiments demonstrated that these cilia detect changes in luminal fluid flow and translate mechanical stimulation into intracellular calcium and cyclic AMP signals, establishing them as bona fide mechanosensors. The polycystin proteins, encoded by genes mutated in polycystic kidney disease, are central to this flow-sensing machinery, a discovery first made in kidney epithelial cells and later extended to the biliary system. On the chemical front, cilia carry an impressive array of receptors: the bitter-taste-like bile acid receptor TGR5 sits in the ciliary membrane, where its precise subcellular localization determines how cholangiocytes respond to bile acid signals, and P2Y12 purinergic receptors allow cilia to detect biliary nucleotides. Osmosensing is handled by ion channels such as TRPV4, which respond to changes in luminal tonicity and trigger bicarbonate secretion, a process critical to maintaining the so-called bicarbonate umbrella that protects cholangiocytes from the detergent-like toxicity of bile acids.

Beyond their sensory role, primary cilia serve as cellular command centres for key developmental and tissue-maintenance signalling pathways. The best studied of these is Hedgehog signalling, which requires the cilium for signal transduction in vertebrate cells. Components of the Hedgehog pathway must traffic through the ciliary compartment for the pathway to be activated, and proteins such as Numb have been shown to positively regulate the signal at the ciliary pocket. In the liver, Hedgehog signalling coordinates the behaviour of hepatic progenitor cells, modulates the response to bile duct injury and even influences hepatic lipid metabolism through GLI transcription factors. Cilia also regulate nutrient and growth pathways including mTORC1, which they control through Lkb1, and they maintain compartmentalized pools of cyclic AMP that differ from those in the rest of the cell, allowing vertebrate cells to interpret ciliary and extracellular cyclic AMP in distinct ways. Critically, cilia are coupled to the cell cycle: most cells resorb their cilium before entering mitosis, and experimental biosensors have shown that cilium persistence after the G1/S transition shapes how cells divide and differentiate.

When the structure or function of cholangiocyte cilia goes awry, the result is a biliary ciliopathy. The most prominent examples are the fibrocystic liver diseases that accompany polycystic kidney disorders. In autosomal recessive polycystic kidney disease, mutations in genes such as PKHD1 and DZIP1L, the latter encoding a transition-zone protein, produce dilated, malformed bile ducts through defective remodelling of the embryonic ductal plate. In autosomal dominant polycystic kidney and liver disease, mutations in genes encoding polycystin-1 and its functional effectors, including the glucosidase II alpha subunit GANAB, drive progressive hepatic cystogenesis. Recent mechanistic work has shown that a transforming growth factor beta axis linking the extracellular matrix to integrin signalling physically reconfigures the bile duct wall to promote cyst expansion, while abnormal positioning of ion transporters and water channels in the cyst-lining epithelium fuels fluid secretion into the cyst lumen. Syndromic ciliopathies add to this spectrum: Meckel-Gruber syndrome, frequently lethal in utero, features absent or defective cilia and gross liver malformations; Bardet-Biedl syndrome and Alström syndrome produce hepatic cystic and fibrotic changes alongside their multisystem features, with the ALMS1 protein shown to regulate TGF-beta signalling and cilium morphology; Joubert syndrome commonly involves congenital hepatic fibrosis; and Sensenbrenner syndrome, a cranioectodermal dysplasia, can progress to end-stage liver disease requiring transplantation.

The reach of ciliary dysfunction extends to acquired and neonatal biliary disease as well. Biliary atresia, the leading indication for paediatric liver transplantation, has long been considered an acquired inflammatory obstruction of the bile ducts, yet genome-wide sequencing of patients has uncovered a broad array of ciliary gene mutations in both syndromic and non-syndromic cases. Morphological studies have repeatedly documented abnormal cholangiocyte cilia in affected infants, and organoid models derived from biliary atresia tissue reveal delayed epithelial development and impaired barrier function. Neonatal sclerosing cholangitis caused by mutations in DCDC2, which encodes a protein that disrupts Wnt signalling when lost, further cements the link between ciliary and biliary pathology. Even in adult medicine, the review points to tantalizing connections: ciliary defects in cholangiocytes trigger sustained epidermal growth factor receptor signalling that drives proliferation and cystic lesions in experimental models, andXIAP-mediated degradation of the IFT protein IFT88 in hepatic stellate cells promotes fibrosis, suggesting that cilium loss in different liver cell populations converges on shared fibrogenic pathways.

Perhaps the most provocative frontier involves liver regeneration and cancer. Cholangiocytes have been identified as facultative liver stem cells capable of replenishing hepatocytes when hepatocyte regeneration fails, and the review argues that primary cilia are central regulators of the biliary regenerative response, including in the context of liver transplantation, where biliary injury, senescence and repair intersect. In cholangiocarcinoma, the outlook is strikingly different: ciliary loss appears to promote tumour growth, driven in part by dysregulated microRNAs that induce overexpression of the deacetylase HDAC6 and a cilia-degrading autophagy process called ciliophagy. Encouragingly, pharmacological HDAC6 inhibition restores ciliary expression and reduces tumour growth in preclinical models, providing proof of principle that the cilium itself can be a drug target. The organelle also participates in DNA damage response and repair, meaning that ciliary status may influence how biliary epithelial cells tolerate the genotoxic stress of chronic inflammation.

The methodological toolbox for studying cilia has expanded dramatically, and the review highlights resources that are accelerating discovery. Curated gene compendia such as CiliaCarta, the SYSCILIA gold standard and the predictive database CilioGenics now catalogue well over a thousand ciliary genes, while spatial proteomics has revealed intrinsic heterogeneity among primary cilia that was previously invisible. Advanced experimental platforms range from conditional mouse models with fluorescently labelled cilia to cholangiocyte organoids and functional ciliated cholangiocytes generated from human pluripotent stem cells, which together allow disease mechanisms to be dissected in human-relevant contexts. Computational simulations of ciliary dynamics in oscillatory flow are refining our understanding of how mechanical signals are encoded, and better fixation protocols are improving the reliability of ciliary immunostaining, an issue that has historically complicated comparisons between studies.

The overarching message of the review is one of therapeutic optimism tempered by unmet need. Most biliary ciliopathies currently lack treatments that address their underlying mechanisms; management relies on symptomatic interventions such as drainage of cysts, transplantation or supportive care. By defining the cilium as a signalling hub where mechanical, chemical and osmotic information converges on pathways such as calcium handling, cyclic AMP signalling, Hedgehog signalling, mTORC1 and TGF-beta, the authors lay the groundwork for interventions that could restore ciliary function or correct the downstream signalling errors it produces. With existing drugs already capable of modulating some of these nodes, and with ciliary biology increasingly understood as a common thread linking inherited fibrocystic disease to acquired conditions like sclerosing cholangitis, biliary atresia and post-transplant strictures, these cellular antennae may soon graduate from anatomical curiosities to clinically actionable targets in hepatology.

Subject of Research: The role of cholangiocyte primary cilia in biliary homeostasis and the pathogenesis of biliary ciliopathies

Article Title: Primary cilia: sensors of biliary homeostasis and disease

Article References: Esser, H., & Ferreira-Gonzalez, S. (2026). Primary cilia: sensors of biliary homeostasis and disease. Nature Reviews Gastroenterology & Hepatology. https://doi.org/10.1038/s41575-026-01262-0

Image Credits: AI Generated

DOI: 10.1038/s41575-026-01262-0

Keywords: primary cilia, cholangiocytes, bile ducts, biliary ciliopathies, intraflagellar transport, polycystic liver disease, Hedgehog signalling, biliary atresia, liver fibrosis, mechanosensing, TGR5, liver regeneration

The story begins in the bone marrow. Bone marrow mesenchymal stromal cells, or BMSCs, are the functional workhorses of the skeletal microenvironment, capable of becoming bone-forming osteoblasts or fat-storing adipocytes. When estrogen levels collapse after menopause, these cells undergo a pathological identity crisis: they senesce, arresting their cell cycles and secreting inflammatory factors, while simultaneously drifting toward abnormal fat production. The result is a marrow increasingly filled with fat instead of bone, a hallmark of the disease. The researchers asked whether circulating bile acids, long known as digestive detergents but increasingly recognized as metabolic signaling molecules, might govern this fate decision.

To find out, the team profiled serum bile acids in healthy donors and postmenopausal osteoporosis patients using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. The comparison revealed a distinct metabolic signature: several bile acids were altered, but hyodeoxycholic acid showed the largest and most consistent reduction in patients. When the researchers stratified patients by their serum levels, those in the low-HDCA group had BMSCs that stained far more strongly for senescence-associated beta-galactosidase and accumulated more lipid droplets during adipogenic induction than cells from high-HDCA patients. Spearman correlation analysis confirmed negative associations between HDCA levels and both senescence and fat accumulation, with tertile stratification showing a dose-dependent relationship.

The next question was whether the molecule could actively reverse the damage, not merely mark it. The researchers established an inflammatory senescence model by exposing patient-derived BMSCs to hydrogen peroxide, then treating them with HDCA at 10, 20, and 40 micromolar concentrations. The results were unambiguous: HDCA dose-dependently reduced senescence staining, suppressed the senescence effectors p53, p21, and p16, and lowered the adipogenic marker FABP4. EdU incorporation assays showed that the compound also rescued the proliferative capacity that oxidative stress had destroyed. Notably, HDCA produced the same protective effects in naturally aged, late-passage BMSCs, suggesting the benefit extends beyond a single laboratory model of injury.

Mechanistically, the team traced a signaling chain that runs from the cell membrane to the nucleus and finally to the mitochondria. Molecular docking simulations predicted that HDCA binds the membrane bile acid receptor TGR5 with higher affinity than the nuclear receptor FXR, and microscale thermophoresis confirmed preferential binding, with a dissociation constant of 26.5 micromolar for TGR5 versus 61.7 micromolar for FXR. As a G protein-coupled receptor, TGR5 activation stimulates cyclic AMP production and protein kinase A signaling. In the senescent BMSCs, HDCA restored TGR5 expression, elevated intracellular cAMP, and increased phosphorylated PKA. Pharmacological blockade with the PKA inhibitor H89 abolished HDCA’s protection, while the TGR5 agonist INT-777 enhanced it, and siRNA knockdown of TGR5 similarly blunted the effect.

Downstream of PKA, an unbiased network pharmacology analysis pointed to a surprising nuclear partner: ESR1, the estrogen receptor alpha. HDCA dose-dependently reversed the hydrogen-peroxide-driven loss of ESR1 protein, but this upregulation failed when PKA was inhibited, placing ESR1 firmly downstream of the TGR5-cAMP-PKA axis. Immunofluorescence showed increased nuclear accumulation of ESR1 after HDCA treatment. When the researchers silenced ESR1 with siRNA, HDCA could no longer suppress lipid accumulation or senescence markers, and p21 rose sharply. In essence, HDCA appears to recapitulate part of estrogen’s protective program in bone stem cells through a non-hormonal route, a finding with obvious implications for patients who cannot take hormone therapy.

The final piece of the mechanism lies in mitochondrial quality control. RNA sequencing of HDCA-treated cells revealed downregulation of p53 pathway genes and enrichment of terms related to oxidative phosphorylation and mitochondrial electron transport. Functional assays showed that HDCA increased colocalization between the autophagosome marker GFP-LC3 and mitochondria labeled with mito-RFP, indicating active mitophagy, the selective disposal of damaged mitochondria. HDCA upregulated the mitophagy mediators PINK1 and Parkin and promoted p62 degradation. A time-course analysis revealed that LC3-II conversion occurred within 12 to 24 hours, while recovery of mitochondrial membrane potential followed at 24 to 48 hours, suggesting that clearing damaged mitochondria precedes functional restoration. Blocking mitophagy with Mdivi-1 abolished HDCA’s protective effects, confirming the pathway’s necessity.

To test whether these cellular findings translate to a living organism, the team used an ovariectomized mouse model that mimics postmenopausal bone loss. After eight weeks of oral HDCA supplementation at 80 milligrams per kilogram per day, micro-CT imaging showed substantially improved trabecular bone volume fraction, bone mineral density, and trabecular number, effects comparable to the clinical bisphosphonate alendronate used as a positive control. Histology revealed that the massive marrow fat infiltration typical of estrogen-deficient mice was markedly suppressed, and immunohistochemistry confirmed reduced p53 and FABP4 signaling in femoral tissue. HDCA also restored TGR5 and ESR1 expression in both intestinal and bone tissues, lowered serum IL-6, and reversed the serum HDCA deficit, implicating the gut-bone axis in the systemic response. Preliminary safety assessments showed no significant changes in body weight, organ indices, or liver and kidney markers over the eight-week treatment.

The authors are careful to frame the work as a foundation rather than a finished therapy. They note that the upstream link between estrogen deficiency and reduced intestinal HDCA production remains untraced, that the in vivo data cannot yet distinguish effects on BMSCs from direct actions on osteoblasts and osteoclasts, and that the mitophagy inhibitor used lacks full specificity, so genetic validation targeting PINK1 or Parkin is still needed. Pharmacokinetics and long-term safety, including effects on the bile acid pool and gut microbial ecology, await dedicated study. The human equivalent dose estimated by allometric scaling, roughly 390 milligrams per day for a 60-kilogram adult, is a theoretical projection that requires formal clinical testing.

Even with those caveats, the study represents a compelling convergence of metabolomics, stem cell biology, and translational medicine. It positions a gut microbiota-derived metabolite as an endogenous regulator of stem cell fate, unifies senescence and aberrant adipogenesis as two faces of the same mitochondrial defect, and demonstrates that a single oral supplement can restore both signaling and structure in a disease model. If future clinical trials validate these findings, the millions of women facing postmenopausal bone loss may one day have an option that works not by forcing bone to grow or blocking its breakdown, but by coaxing their own aging stem cells back to youthfulness from within.

Subject of Research: Bile acid metabolism and bone marrow mesenchymal stem cell rejuvenation in postmenopausal osteoporosis

Article Title: Hyodeoxycholic acid rejuvenates BMSCs against postmenopausal osteoporosis by attenuating senescence and aberrant adipogenesis via TGR5-ESR1-mediated mitophagy

Article References: Zeng, C., Yu, W., Kang, Y., Liu, W., Chen, Z., Xiao, Z., Liu, Z., Zhang, W., Li, Q., Zeng, Y., Li, Z., Pan, B., Xie, Z., & Zhang, Z. (2026). Hyodeoxycholic acid rejuvenates BMSCs against postmenopausal osteoporosis by attenuating senescence and aberrant adipogenesis via TGR5-ESR1-mediated mitophagy. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.020

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.020

Keywords: postmenopausal osteoporosis, hyodeoxycholic acid, bile acids, bone marrow mesenchymal stem cells, TGR5, ESR1, mitophagy, PINK1, Parkin, gut-bone axis, cellular senescence, adipogenesis

FXR, the farnesoid X receptor, is expressed predominantly in the liver, intestine, and kidneys, and functions as the body’s principal bile acid sensor. Its endogenous ligands are bile acids themselves, with binding potency following a clear hierarchy: chenodeoxycholic acid is the strongest activator, followed by deoxycholic acid, lithocholic acid, and finally cholic acid. Once activated, FXR operates a sophisticated transcriptional network that keeps bile acid levels in check. In the liver, it ramps up production of the small heterodimer partner, a transcriptional repressor that shuts down CYP7A1 and CYP8B1, the two enzymes that drive bile acid synthesis. In the intestine, FXR triggers the release of fibroblast growth factor 15 in rodents and 19 in humans, which travels through the portal vein to the liver and binds the FGFR4 receptor complex to suppress bile acid production through a second, independent route. The review emphasizes that this dual feedback system is most powerful in the liver, with weaker but meaningful effects in the small intestine and kidneys.

Beyond bile acid chemistry, FXR acts as a metabolic conductor. Activation of the receptor suppresses SREBP-1c, the master switch for fatty acid and triglyceride synthesis, through SHP-dependent signaling, while simultaneously boosting PPARα activity to upregulate carnitine palmitoyl transferase 1 and accelerate fat burning through beta-oxidation. FXR also reshapes the fatty acid profile of the liver, lowering both monounsaturated and polyunsaturated fatty acid levels through distinct mechanisms. Its influence extends to glucose: protein kinase A-mediated phosphorylation of FXR activates gluconeogenic gene expression, while intestinal FXR stimulates secretion of glucagon-like peptide-1, the incretin hormone made famous by blockbuster diabetes and obesity drugs, thereby promoting insulin release and improving glucose tolerance. The receptor additionally damps inflammation by suppressing NF-κB signaling, reducing interleukin-6 and interleukin-1β, and by directly blocking the assembly of the NLRP3 inflammasome through SHP, preventing caspase-1 activation and the pyroptotic cell death that fuels hepatic inflammation.

The clinical implications of these mechanisms are enormous. In cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis, where toxic bile acids accumulate and destroy tissue, FXR agonists have been the leading therapeutic strategy for years. Obeticholic acid, a derivative of chenodeoxycholic acid, became the first approved FXR agonist for primary biliary cholangitis in 2016 and showed promise in metabolic dysfunction-associated steatohepatitis as well. Yet the review delivers a striking update: amid persistent safety concerns and disappointing results in the COBALT trial, the manufacturer voluntarily withdrew obeticholic acid from the United States market in September 2025. Hepatotoxicity, severe pruritus, and unfavorable lipid changes had outweighed its benefits. The withdrawal casts a long shadow over the field and underscores why newer agents such as cilofexor, tropifexor, and vonafexor—each designed for better selectivity and tolerability—remain in various stages of clinical development, some already halted for lack of efficacy and others still advancing.

In fatty liver disease, the review describes FXR as a reliable intervention point operating through multiple converging pathways. The receptor inhibits fat production via the FXR-SHP-SREBP1c axis, promotes fat oxidation through PPARα, and induces detoxification enzymes such as CYP3A4 and sulfotransferase 2A1 to enhance bile acid clearance. Intriguingly, FXR also participates in a reciprocal positive feedback loop with SIRT1, the longevity-associated histone deacetylase: FXR induces SHP, which suppresses microRNA-34a and thereby lifts the brake on SIRT1 expression, while SIRT1 in turn deacetylates FXR, stabilizing it and promoting its nuclear translocation. Intestinal FXR adds another layer of protection by maintaining epithelial tight junctions, preserving the gut vascular barrier through Wnt/beta-catenin signaling, and upregulating antimicrobial defenses. In liver cancer, the evidence is equally compelling. Mice lacking FXR spontaneously develop hepatocellular carcinoma with bile acid accumulation and elevated beta-catenin target genes, and FXR activation directly disrupts the beta-catenin-TCF4 transcriptional complex while also suppressing tumor progression through the JAK2-STAT3 pathway and the FGF15/19-FGFR4 axis.

TGR5, the review’s second protagonist, tells a complementary story through entirely different cell biology. Rather than sitting in the nucleus, TGR5 is embedded in the plasma membrane, where bile acid binding triggers cyclic AMP production within seconds. It is distributed widely across the liver, gallbladder, intestine, kidney, spleen, brain, skeletal muscle, and brown adipose tissue, with ligand potency ranking lithocholic acid highest, followed by deoxycholic acid, chenodeoxycholic acid, and cholic acid. In metabolic terms, TGR5 activation promotes GLP-1 secretion from intestinal endocrine cells, enhances insulin sensitivity, and induces the browning of white adipose tissue. The review details two thermogenic mechanisms: cAMP-PKA signaling enhances the conversion of thyroid hormone T4 to the active T3, upregulating uncoupling protein 1 and driving mitochondrial heat production, while a parallel pathway induces mitochondrial creatine kinase 2 to establish a UCP1-independent futile creatine cycle. Together these actions increase energy expenditure and counteract obesity.

TGR5 also functions as an immunological brake. Its activation inhibits NF-κB and NLRP3 inflammasome signaling through the cAMP-PKA axis, steering macrophages away from the pro-inflammatory M1 phenotype and toward the reparative M2 state. In models of cholestasis induced by bile duct ligation, TGR5 knockout worsened oxidative stress and Kupffer cell polarization, while TGR5 agonists reduced damage by inhibiting NF-κB and activating the Nrf2/HO-1 pathway. In cancer, TGR5-deficient mice proved more susceptible to chemically induced liver cancer, and receptor activation suppressed tumor development through STAT3 inhibition. Agonist development, however, remains early: the semi-synthetic bile acid analog INT-777 has never entered human trials, while the next-generation candidate RDX8940 shows potent activity against insulin resistance and hepatic steatosis in preclinical models but still lacks human safety data. Antagonists such as SBI-115 and SBI-364, meanwhile, have revealed unexpected value in polycystic kidney and liver disease, where excessive TGR5 signaling drives aberrant bile duct proliferation.

Perhaps the review’s most important contribution is its portrait of FXR and TGR5 as an interlocking system rather than two isolated targets. The two receptors coordinate bile acid homeostasis, with FXR providing the slow transcriptional feedback and TGR5 handling rapid metabolic responses. Along the gut-liver axis, bile acids activate FXR in enterocytes to release FGF15/19 while simultaneously engaging TGR5 on intestinal L cells to secrete GLP-1, and gut microbes remodel bile acid structures into conjugates that can activate both receptors at once. During liver regeneration, knockout of either receptor delays recovery, indicating partial functional compensation that is not fully interchangeable. In the intestinal epithelium the two receptors actually pull in opposite directions—FXR restrains proliferation through cell-cycle inhibitors like p21 while TGR5 promotes it through cAMP-PKA and EGFR crosstalk—creating a delicate balance that maintains tissue homeostasis.

The review closes with a candid assessment of the obstacles ahead. Only a small fraction of FXR- and TGR5-targeted drugs have reached clinical use, and most candidates suffer from low bioavailability, short duration of action, or side effects such as pruritus, dyslipidemia, and hepatotoxicity. FXR biology is strikingly tissue-dependent: only about 11 percent of FXR binding sites are shared between mouse liver and intestine, and while single-organ knockout produces mild phenotypes, double knockout causes severe cholestatic injury, revealing that hepatic and intestinal FXR cannot substitute for one another. TGR5’s role in primary sclerosing cholangitis remains genuinely contested, with evidence both for cholangiocyte-protective and disease-promoting functions depending on context. The authors call for deeper mechanistic mapping of cell-type-specific receptor functions, next-generation dual-target modulators, combination strategies with GLP-1 receptor agonists, and rigorously designed trials. For a field still reeling from obeticholic acid’s withdrawal, the message is clear: bile acid receptors remain among the most promising targets in hepatology, but realizing that promise will require matching the elegance of the biology with equally sophisticated pharmacology.

Subject of Research: The roles of the bile acid receptors FXR and TGR5 in hepatic steatosis, fibrosis, cholestatic disease, and hepatocellular carcinoma

Article Title: The Bile Acid Signaling Axis: Deciphering the Roles of FXR and TGR5 in Hepatic Steatosis, Fibrosis, and Cancer

Article References: Liu, J., Sun, K., Liu, H., Zhu, M., Li, C., He, Y., & Qin, L. (2026). The Bile Acid Signaling Axis: Deciphering the Roles of FXR and TGR5 in Hepatic Steatosis, Fibrosis, and Cancer. Pharmacology Research & Perspectives, 14(5), Article e70318. https://doi.org/10.1002/prp2.70318

Image Credits: AI Generated

DOI: 10.1002/prp2.70318

Keywords: bile acids, FXR, TGR5, liver fibrosis, hepatocellular carcinoma, MASLD, MASH, cholestasis, obeticholic acid, GLP-1, NF-kB, gut-liver axis

The review, led by Minho Seo and Jae-Hyeon Lee of Konkuk University together with colleagues under the supervision of Jooho Park, traces the mechanistic foundations that make bile acids such versatile drugs. Their biological effects are mediated largely through a set of dedicated receptors: the nuclear farnesoid X receptor, or FXR, which acts as a master homeostat for hepatic nutrient metabolism, and the cell-surface G-protein-coupled receptor TGR5, also known as GPBAR1, which links bile acid sensing to energy expenditure and immune tone. Activation of TGR5 in enteroendocrine cells promotes glucagon-like peptide-1 secretion, a pathway of intense interest for diabetes and obesity, while FXR signaling suppresses bile acid synthesis and orchestrates the enterohepatic feedback loop that keeps the bile acid pool in check. Additional receptors, including the pregnane X receptor, the constitutive androstane receptor, the vitamin D receptor, and the sphingosine-1-phosphate receptor 2, broaden the signaling repertoire considerably.

Structural biology has sharpened these targets considerably in recent years. High-resolution structures of the bile acid transporter NTCP, which doubles as the receptor for hepatitis B and D viruses, and of the apical sodium-dependent bile acid transporter, ASBT, have revealed the molecular details of how bile acids are shuttled across membranes. Crystallographic snapshots of GPBAR activation have likewise clarified how subtle differences in the steroidal scaffold translate into receptor selectivity. This structural knowledge underpins the design of transporter-targeted delivery systems, in which bile acid motifs are grafted onto drugs to hijack the body’s own recycling machinery, allowing orally administered molecules, including large peptides, to cross the intestinal epithelium through transporter-mediated endocytosis.

The clinical track record of bile acid therapeutics is already substantial. Ursodeoxycholic acid has been a mainstay for cholestatic liver disease for decades, and its semisynthetic relatives, including norursodeoxycholic acid, have shown anticholestatic and anti-inflammatory effects in models of sclerosing cholangitis and fatty liver disease. Obeticholic acid, a potent semisynthetic FXR agonist derived from chenodeoxycholic acid, demonstrated significant improvements in patients with primary biliary cholangitis in a placebo-controlled trial and has been evaluated extensively in non-alcoholic steatohepatitis, now termed metabolic dysfunction-associated steatohepatitis, or MASH. Phase 2 and phase 3 studies of obeticholic acid in fibrotic NASH showed reductions in hepatic injury markers, even as the community continues to weigh long-term safety and lipid effects.

Alongside these steroidal agonists, a wave of non-bile acid FXR modulators has entered the clinic. Tropifexor, a highly potent non-bile acid agonist, was well tolerated in healthy volunteers and abrogated steatohepatitis and fibrosis in rodent models through an antioxidative gene expression profile. EDP-305, another non-bile acid agonist, potently suppressed liver injury and fibrosis in preclinical studies and advanced into a phase 2 dose-ranging trial in NASH patients, while MET409, a structurally optimized FXR agonist, reduced liver fat content over twelve weeks in patients. Dual agonists such as INT-767, which activates both FXR and TGR5, and BAR502, which promotes browning of white adipose tissue while reversing liver steatosis and fibrosis, illustrate the trend toward multi-receptor engagement. The review emphasizes that improving receptor selectivity and tissue specificity remains the central medicinal chemistry challenge in this field.

Cholestatic disease has also been transformed by a different class of bile acid-directed drugs: the ileal bile acid transporter inhibitors. By blocking ASBT-mediated reabsorption in the terminal ileum, agents such as odevixibat, maralixibat, and linerixibat increase fecal bile acid excretion and reduce the toxic pool circulating in cholestatic liver. Odevixibat has shown benefit in phase 3 trials of progressive familial intrahepatic cholestasis and received regulatory approval for associated pruritus, while maralixibat demonstrated efficacy in Alagille syndrome and in a multicenter phase 3 trial of progressive familial intrahepatic cholestasis. Norursodeoxycholic acid improved cholestasis in primary sclerosing cholangitis, and recent work characterizing the carrier cross-reactivity profiles of these inhibitors is helping clinicians match the right molecule to the right patient population.

Perhaps the most visually striking frontier described in the review is the use of bile acids as building blocks for drug delivery. Their facial amphiphilicity, one hydrophobic face and one hydrophilic face on the same rigid steroid, makes them superb self-assembling units. Researchers have exploited this to create drug conjugates, polymeric carriers, peptide-based platforms, and nanostructured delivery systems. Cholic acid-conjugated oxaliplatin has been developed as a liver-targeted prodrug, glycocholic acid-modified micelles have enabled oral delivery of gemcitabine, and ursodeoxycholic acid-based molecular blocks respond to the acidic tumor microenvironment. Catechol-modified bile acid conjugates have been engineered into pH-responsive nanoparticles that exploit ASBT for intestinal uptake, and charge-based supramolecular peptide nanocomplexes have been designed for oral delivery via transporter-driven endocytosis, a strategy relevant to biologics such as semaglutide and liraglutide.

Bile acid chemistry is even reaching into oncology and immunotherapy. Ursodeoxycholic acid platinum(IV) conjugates have been reported as antiproliferative and antimetastatic agents that remodel the tumor microenvironment by suppressing JAK2/STAT3 signaling. Self-assembled nanocrystals combining obeticholic acid with atorvastatin accumulate in the liver and potentiate treatment of metabolic-associated fatty liver disease. Bile acid-containing lipid nanoparticles have been shown to enhance extrahepatic mRNA delivery, an intriguing twist for the mRNA medicine field, while facially amphiphilic bile acid-functionalized antimicrobials combat pathogenic bacteria, fungi, and their biofilms. Bone tissue engineering based on bile acid scaffolds rounds out a materials portfolio that extends far beyond the gut and liver.

The review also situates bile acids within the ecology of the gut microbiome, an area that has exploded in the past decade. Microbial enzymes, including bile salt hydrolases that catalyze the formation of amine-conjugated bile acids, dramatically expand the chemical diversity of the bile acid pool, and microbiome-driven dehydroxylation pathways generate species with distinct receptor activities. Because microbial bile acid modulation shapes host metabolism, immunity, and digestive health, the authors note that future therapeutics may need to be designed with the microbiome in mind, either by resisting microbial transformation or by deliberately harnessing it. This systems-level perspective reinforces the idea that bile acids function less like simple detergents and more like a distributed endocrine signaling network.

Looking ahead, the authors argue that continued innovation in receptor-selective derivatives and transporter-targeted delivery systems should accelerate clinical translation, particularly for hepatobiliary, metabolic, and oncological diseases. The outstanding barriers are familiar ones: oral bioavailability for large conjugates, tissue-specific targeting that avoids off-target receptor activation, and long-term clinical safety, especially for chronic metabolic indications. With the structural biology of transporters and receptors now largely solved, and with biomaterial engineering supplying an expanding toolbox of conjugates and nanocarriers, the field appears positioned to convert a century-old physiological curiosity into a next-generation therapeutic platform, one rigid steroidal scaffold at a time.

Subject of Research: Bile acid-based therapeutics, including semisynthetic derivatives, receptor agonists, and bile acid-inspired drug delivery systems

Article Title: Bile acid-based therapeutics: recent advances in bile acid conjugates and derivatives

Article References: Seo, M., Lee, J.-H., Yang, S.-B., Ma, G., Lee, H., Han, J., Ryu, Y., & Park, J. (2026). Bile acid-based therapeutics: recent advances in bile acid conjugates and derivatives. Journal of Pharmaceutical Investigation. https://doi.org/10.1007/s40005-026-00830-5

Image Credits: AI Generated

DOI: 10.1007/s40005-026-00830-5

Keywords: bile acids, FXR agonists, TGR5, bile acid transporters, obeticholic acid, cholestasis, MASH, drug delivery, nanoparticles, gut microbiome, drug conjugates, pharmaceutical research

The article begins with the fundamentals of bile acid physiology. Roughly 95 percent of the bile acids secreted into the intestine are actively reabsorbed in the ileum and recycled back to the liver through the portal vein, a circuit known as the enterohepatic circulation. Primary bile acids, chiefly cholic acid and chenodeoxycholic acid, are synthesized from cholesterol in the liver through pathways driven by the enzymes CYP7A1 and CYP27A1. Once they reach the intestine, gut bacteria convert them by dehydroxylation into secondary bile acids such as deoxycholic acid and lithocholic acid. These microbial derivatives do not simply linger in the gut; they enter the systemic circulation and exert far-reaching effects on host metabolism, intestinal health and inflammatory tone.

The mechanistic heart of the commentary lies in the receptors through which bile acids act. The farnesoid X receptor, or FXR, is a nuclear receptor abundant in liver, intestine and kidney that functions as the body’s bile acid thermostat. When bile acid concentrations rise, FXR binds them and triggers a negative feedback loop that suppresses CYP7A1, curbing further synthesis and preventing toxic accumulation. But FXR’s portfolio extends well beyond metabolic housekeeping. The authors highlight evidence that FXR activation restrains tumor invasion by downregulating matrix metalloproteinases, enzymes that degrade the extracellular matrix, and by dampening pro-inflammatory signaling and cell-cycle progression. The FXR agonist obeticholic acid, already validated in a phase 3 trial for non-alcoholic steatohepatitis, is flagged as a candidate for cancer therapy, potentially in combination with conventional chemotherapy.

A second receptor, TGR5, operates through entirely different circuitry. As a G protein-coupled receptor expressed on immune cells, intestinal epithelial cells and adipose tissue, TGR5 mediates non-genomic, rapid signaling. Its activation raises intracellular cyclic AMP, promotes thermogenesis in brown fat, improves insulin sensitivity and, critically, can halt the runaway proliferation of cancer cells by interfering with cell-cycle progression. TGR5 also modulates macrophages and T cells within the tumor microenvironment, reducing the chronic inflammation that fuels tumor growth. Together, the authors contend, FXR and TGR5 represent a paired molecular handle for therapeutic intervention in bile acid signaling.

The commentary is equally candid about bile acids’ dark side. Secondary bile acids such as deoxycholic acid can be frankly carcinogenic at high concentrations, particularly when they persist in the intestine for extended periods. They induce the production of reactive oxygen species, generating oxidative stress that damages DNA, proteins and lipids and seeds the mutations from which cancers arise—a mechanism considered especially relevant to colorectal cancer. Deoxycholic acid can also activate the Wnt/beta-catenin pathway, driving proliferation while suppressing apoptosis, and both deoxycholic and lithocholic acid trigger the release of pro-inflammatory cytokines such as TNF-alpha and IL-6 through JAK/STAT and NF-kappaB signaling. Chronic inflammation of this kind is regarded as a major pathogenic mechanism in digestive tract cancers, including colorectal and esophageal malignancies.

Woven through the analysis is the bidirectional relationship between bile acids and the gut microbiome. Bile acids shape which microbes thrive: their amphipathic structure allows them to disrupt bacterial membranes, induce DNA damage and provoke oxidative stress in susceptible organisms, while bacteria that express bile acid-metabolizing enzymes gain a survival advantage. In turn, microbes chemically transform bile acids. Bacteria secreting bile salt hydrolases cleave the glycine or taurine groups from conjugated bile acids, converting them into free bile acids with altered solubility and biological activity. Recent work has even uncovered entirely novel microbial bile acid species, such as the succinylated bile acid 3-sucCA, which promotes the growth of the beneficial bacterium Akkermansia muciniphila by regulating its glucose-utilizing NagB enzyme. The authors note that much remains to be learned about how manipulating the bile acid pool reshapes host-microbe communication.

One of the most provocative threads in the commentary concerns taurine, the amino sulfonic acid conjugated to many bile acids. Long celebrated as an antioxidant that neutralizes reactive oxygen species, protects DNA integrity and restrains inflammation by inhibiting NF-kappaB and steering macrophages away from a pro-inflammatory M1 phenotype, taurine has generally been viewed as protective against cancer. Studies cited in the article show it can downregulate cyclins D1 and E and inhibit CDK4 and CDK6, blocking the G1-to-S transition and slowing tumor cell proliferation. Approximately 20 percent of the body’s taurine pool derives from the breakdown of taurine-conjugated bile acids, tying this amino acid intimately into bile acid metabolism.

Yet the picture is not so simple. The authors spotlight a 2024 Cell study identifying the taurine transporter SLC6A6 as a determinant of gastric cancer progression and recurrence. Tumor cells overexpress SLC6A6 and outcompete CD8-positive T cells for taurine, starving the immune cells and driving their exhaustion. Mechanistically, taurine depletion in T cells heightens endoplasmic reticulum stress, activating PERK-JAK1-STAT3 signaling and the transcription factor ATF4, which switches on multiple immune checkpoint genes. In gastric cancer, chemotherapy can upregulate the transcription factor SP1, further boosting SLC6A6 expression and intensifying this nutritional competition—a mechanism that may underlie both immune dysfunction and chemotherapy resistance. Taurine supplementation, the authors suggest, could serve as an adjunct therapy by protecting T cells and enhancing chemotherapy efficacy, but only in the right context.

That context-dependence is the commentary’s central message. Taurine’s function, like that of bile acids generally, is jointly determined by microenvironmental conditions, cell-type-specific metabolic capacity and host immune status—not by any single molecular property. This framing aligns with the integrative medicine philosophy articulated by Academician Daiming Fan, whose concepts of anti-cancer treatment, tumor control and life support emphasize restoring the body’s intrinsic regulatory forces rather than simply eliminating lesions. From this perspective, bile acid dysregulation is both a marker and a driver of the systemic imbalance that underlies cancer, and the liver-gut-immune axis becomes a concrete intervention point: modifying bile acid composition through diet, nutritional support or metabolic regulation may help rebuild an antitumor immune environment and ease treatment-related side effects.

The authors conclude that a multidimensional strategy centered on bile acid signaling offers a route from treating cancer as a local lesion toward managing it as a disorder of systemic homeostasis. By integrating molecular mechanisms with lifestyle and supportive therapies, and by individualizing approaches to taurine and bile acid pathways rather than applying blanket supplementation or inhibition, the framework points toward a more holistic, patient-centered integrative oncology—one in which the humble detergent molecules of digestion are recognized as key arbiters of life and disease.

Subject of Research: The roles of bile acids, their receptors and taurine metabolism in cancer biology and integrative oncology

Article Title: An integrative view of bile acids

Article References: Bai, X., Liu, B., Liu, L., Lu, Y., & Zhao, X. (2026). An integrative view of bile acids. Holistic Integrative Oncology, 5(1), Article 67. https://doi.org/10.1007/s44178-026-00290-9

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00290-9

Keywords: bile acids, FXR, TGR5, gut microbiota, taurine, SLC6A6, tumor microenvironment, colorectal cancer, obeticholic acid, integrative oncology, bile salt hydrolase, immune evasion