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