A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Abstract Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3,4,5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912,13,14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases. This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription £17.99 / 30 days cancel any time Subscribe to this journal Receive 52 print issues and online access £199.00 per year only £3.83 per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. £ 29.95 Prices may be subject to local taxes which are calculated during checkout Data availability The crystal structure of the FXR–linafexor complex bound to the second LXXLL peptide motif from SRC2 has been deposited in the PDB under PDB ID 9LQ3. Superposition of the linafexor-bound FXR complex with the tropifexor-bound structure can be found under PDB ID 7D42. The transcriptomics data were uploaded to the National Genomics Data Center (https://ngdc.cncb.ac.cn/gsa/; reference ID CRA038114). Source data are provided with this paper. References Evans, R. 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XDB0830000 and XDB37030103 to H.E.X.); The National Natural Science Foundation of China (grant nos. 32130022 and 82121005 to H.E.X, and 82521004 and 82130099 to J.L.); The National Key R&D Program of China (grant no. 2022YFC2703105 to H.E.X.); Shanghai Outstanding Academic Leader Program (grant no. 23XD1450800 to Y. Zang); Shanghai Eastern Talents Excellence Program to Y. Zang; Shanghai Municipal Science and Technology Major Project (grant no. 2019SHZDZX02 to H.E.X.); Shanghai Super Postdoctoral Fellowship Program to B.T.; The Lingang Laboratory (grant no. LG-GG-202204-01 to H.E.X., and LG202103-03 to Y. Zang); National Key R&D Program ‘Strategic Scientific and Technological Innovation Cooperation’ Key Project (grant no. 2022YFE0203600 to H.E.X.). Author information Authors and Affiliations Contributions H.E.X and J.L. conceptualized the work. H.E.X, Y. Zang, Y.L. and J.L. acquired funding. Y. Zang, J.S., G.Z., B.T., M.L., B.Y., G.W., H.P., S.Y., R.D., Y. Zhao, Z.Z., H.-R.G., D.-D.S., H.W., L.G., J.Y., X.D. and Y.L. administered the project. H.E.X. and J.L. supervised the work. Y. Zang, J.S., G.Z., B.T., H.-R.G., H.P., X.D., Y.L. and H.E.X. wrote the original draft, which was reviewed and edited by Y. Zang, H.E.X., Y.L. and J.L. Corresponding authors Ethics declarations Competing interests Y. Zang, J.S., D.-D.S., L.G., J.L., H.E.X. and Cascade Pharmaceuticals (of which Z.Z. and H.E.X. are co-founders, and G.Z., G.W., H.P., S.Y., R.D. and Y. Zhao are employees) have filed patents on linafexor (PCT/CN2020/085713, PCT/CN2021/121313, US12240841B2 and CN 114315830 B). The remaining authors declare no competing interest. Peer review Peer review information Nature thanks Jakub Bijak, Bistra Dilkina, Van C. Tran and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Additional information Extended data figures and tables Extended Data Fig. 1 Synthetic route for the preparation of linafexor. Shown is the multi-step synthetic scheme for linafexor (CS0159). Reagents and conditions: (a) K2CO3, DMSO, 130 °C; (b) i: NH2OH·HCl, K2CO3, EtOH/H2O, 90 °C; ii: N-chlorosuccinimide, DMF, r.t.; (c) Et3N, EtOH, r.t.; (d) i: DIBAL-H, THF, N2, 0 °C; ii: CBr4, PPh3, DCM, r.t.; (e) t-BuOK, THF, 0 °C; (f) i: NH2OH·HCl, Et3N, EtOH, 80 °C; ii: CDI, DBU, 1,4-dioxane, 100 °C. Extended Data Fig. 2 Proposed metabolic pathways of linafexor. Linafexor at the concentration of 10 µM, was incubated with liver microsomes at 37 °C for 10 min in the presence of NADPH. Based on the metabolite identification, the major metabolic pathways in mouse, rat, dog, monkey, and human liver microsomes of linafexor was mono-oxidation. In addition to the unchanged linafexor (MW = 571.43), eleven metabolites of linafexor were detected and identified by LC-UV-MSn (n = 1-2) from mouse, rat, dog, monkey, and human liver microsomes. The metabolites were assigned as M305a (the O-dealkylated product of parent drug), M305b (the mono-oxidized and O-dealkylated product of parent drug), M303 (the dealkylated and dehydrogenated product of parent drug), M604 (the di-oxidized and hydrogenated product of parent drug), M586c/d/e/f/g/h (the mono-oxidized product of parent drug), M568 (the mono-oxidized and defluorinated product of parent drug). M, mouse liver microsomes (MLM); R, rat liver microsomes (RLM); D, dog liver microsomes (DLM); C, cynomolgus monkey liver microsomes (CLM); H, human liver microsomes (HLM). Extended Data Fig. 3 In Vitro Metabolism of linafexor in Human Liver Microsomes and Recombinant CYP Enzyme Systems. (A) The chemical inhibition reaction of linafexor examined in the presence and absence of the CYP isozyme-selective chemical inhibitors in human liver microsomes (HLM). n = 3 per group. (B) The metabolism of linafexor catalysed by the various recombinant human cytochrome P450 (CYP) enzyme systems. n = 3 per group. Data are depicted as mean ± SEM. Extended Data Fig. 4 Efficacy of linafexor in CDAHFD fed rats with advanced liver fibrosis. (A) A schematic representation of the rat model for advanced liver fibrosis induced by CDAHFD. Mice were assigned to five groups: Naïve (n = 6), vehicle (n = 6), Lina 0.1 mpk (n = 6) and Lina 0.3mpk (n = 5). Quantitative analysis of (B) serum alanine aminotransferase (ALT), (C) serum aspartate aminotransferase (AST), (D) serum total cholesterol (TC), and (E) serum low-density lipoprotein cholesterol (LDL-C) levels. (F) Representative images depicting Sirius Red staining of liver tissue. (G) Quantification of areas positive for Sirius Red staining. Scale bar: 100 μm. (H) Quantification of the percentage of α-smooth muscle actin (α-SMA) positive area in liver tissue sections. (I) Representative images illustrating α-SMA staining in liver tissue. Scale bar: 100 μm. Significance was assessed by ordinary one-way ANOVA with Fisher’s LSD test (B-C, D-E, G-H),. Data are depicted as mean ± SEM. Extended Data Fig. 5 Efficacy evaluation of linafexor in a murine model of metabolic-associated steatosis hepatitis (MASH) induced by the combination of GAN diet and CCl4. (A) A schematic representation of the rat model for advanced liver fibrosis induced by GAN+CCl4. Mice were assigned to three groups: Naïve (n = 8), vehicle (n = 10), Lina 0.2 mpk (n = 8). The quantitative assessment of (B) serum alanine aminotransferase (ALT), (C) serum aspartate aminotransferase (AST), (D) serum low-density lipoprotein cholesterol (LDL-C), (E) liver triglycerides (TG), (F) liver total cholesterol (TC), and (G) hydroxyproline (HYP) levels in rats with metabolic-associated steatotic hepatitis (MASH). (H) Representative images of hematoxylin-eosin (H&E) staining of liver sections from MASH rats. Quantification of the (I) steatosis score, (J) inflammation score, and (K) ballooning scores. (L) Representative images of Sirius Red staining. (M) Quantification of the ratio of Sirius Red-positive areas in tissue slices. (N) The representative illustrations of the α-smooth muscle actin (α-SMA) positivity area, and (O) the quantification of the ratio of α-SMA positive areas in tissue slices. The scale bar is set at 100 μm. Data are expressed as mean ± standard error of the mean (SEM). Statistical significance is indicated as follows: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 when compared to the model group. Mpk: milligrams per kilogram (mg/kg). Extended Data Fig. 6 Histological Analysis of Liver Injury and Fibrosis in PBC and PSC Murine Models treated with linafexor. (A) Representative liver histology of hepatocellular necrosis related to Fig. 3 R in PBC mice model. Scale bar 50 μm. Abbreviations: ANIT, alpha-naphthy lisothiocyanate; UDCA, Ursodeoxycholic acid; OCA, Obeticholic acid; Trop, tropifexor; Lina, linafexor. (B) Representative Sirius Red staining related to Fig. 3 X in PSC mice model. Scale bar 50 μm. Abbreviations: DDC, 3,5-diethoxycarbonyl 1,4-dihydrocollidine; UDCA, Ursodeoxycholic acid; OCA, Obeticholic acid; Cilo, Cilofexor; Lina, linafexor; mpk: mg/kg. Extended Data Fig. 7 Efficiency study of linafexor in ANIT induced PBC mice. (A) PK profile of linafexor given once a day (QD) and every other day (Q2D) on day 1 and day 7 (n = 3 per group). (B) PK profile of linafexor given by Osmotic pumps (n = 3 per group). (C) Liver weight and (D) liver index of different dosing methods (n = 7 per group). (E) Serum ALT, (F) serum AST, (G) serum ALP, (H) serum TBIL and (I) serum TBA of different dosing methods. (J) Hepatocellular necrosis and (K) representative images of liver HE stain of different dosing methods. Significance was assessed by ordinary one-way ANOVA with Fisher’s LSD test (C-J). Data are depicted as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Extended Data Fig. 8 Dose selection of linafexor in ANIT induced PBC mice and DDC induced PSC mice. (A-G) Different dosing in PBC mice model. Mice were assigned to six groups: Naïve (n = 6), vehicle (n = 10), Lina 0.04 mpk (n = 10), Lina 0.2 mpk (n = 10), Lina 1 mpk (n = 9), UDCA 100mpk (n = 9). (A) Serum ALT, (B) serum AST, (C) serum ALP, (D) serum TBIL, (E) serum TBA, (F) percentage of hepatocellular necrosis and (G) representative images of liver HE stains. (H-M) Different dosing in PSC mice model. Mice were assigned to six groups: Naïve (n = 10), vehicle (n = 10), Lina 0.04 mpk (n = 10), Lina 0.2 mpk (n = 10), Lina 1 mpk (n = 10), OCA 30mpk (n = 10). (H) Serum ALT, (I) serum AST, (J) serum ALP, (K) serum TBIL, (L) serum TBA, (M) percentage of sirus red positive area and (G) representative images of liver sirus red stains. Significance was assessed by ordinary one-way ANOVA with Fisher’s LSD test (A-F, H-M), Data are depicted as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Extended Data Fig. 9 Gene expression profiles induced by linafexor and OCA. (A) The numbers of differentially expressed genes (DEGs) at time points of 2 h, 4 h, 8 h, 18 h and 24 h following the acute treatment of OCA, compared to the control groups respectively in wild-type mice. (B) Venn diagrams showing overlap of DEGs between linafexor vs Control and OCA vs Control groups at 2 h and 24 h post-administration in wild-type mice. (C) Pathway enrichment analysis of the DEGs in the OCA treatment group versus the control group, at 2 h, 4 h, 8 h, 18 h and 24 h post-acute treatment (D) The heatmaps illustrating the expression levels of upregulated and downregulated genes in response to linafexor compared to the control group at various time points: 2 h, 4 h, and 8 h following acute treatment. (E) Time-course expression profiles of FXR and its downstream targets (SHP, MAFG, CYP7A1, CYP8B1, BSEP) following acute administration of linafexor and OCA. The green circle labelled as linafexor showed no alteration in the indicated gene expression at 24 h post-administration, while the red circle labelled as OCA exhibited altered gene expression at the same time point. Data are depicted as mean ± SEM. Extended Data Fig. 10 Gene expression profiles induced by linafexor and tropifexor. (A) The heatmaps illustrating the expression levels of downregulated genes in response to linafexor compared to the control group at various time points: 2 h, 4 h, and 8 h following acute treatment. (B) The heatmaps illustrating the expression levels of downregulated genes in response to linafexor compared to the vehicle group at various time points: 2 h, 4 h, and 8 h post-final treatment after a 4-week administration within a MASH murine model induced by the GAN diet combined with CCl4. Extended Data Fig. 11 The pharmacokinetic characteristics of linafexor on the first day of administration in humans, followed by a regimen of multiple ascending doses (MAD) with once-daily (QD) dosing. 0.4 mg, 1 mg, 2 mg (n = 6), 4 mg (n = 5). Data are depicted as mean ± SEM. Supplementary information Supplementary Information (download PDF ) Supplementary Methods and Tables 1–12. Rights and permissions About this article Cite this article Zang, Y., Shi, J., Zhao, G. et al. A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases. Nature (2026). https://doi.org/10.1038/s41586-026-10633-1 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1038/s41586-026-10633-1