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1. Evans, R. M. & Mangelsdorf, D. J. Nuclear Receptors, RXR, and the Big Bang. Cell 157, 255–266 (2014). 2. Huang, P., Chandra, V. & Rastinejad, F. Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics. Annu. Rev. Physiol. 72, 247–272 (2010). 3. Khorasanizadeh, S. & Rastinejad, F. Visualizing the Architectures and Interactions of Nuclear Receptors. Endocrinology 157, 4212–4221 (2016). 4. Claudel, T. et al. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J. Clin. Invest. 109, 961–971 (2002). 5. Mi, L., J. et al. Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR. Mol. Cell 11, 1093–1100 (2003). 6. Huang, P., Chandra, V. & Rastinejad, F. Retinoic Acid Actions through Mammalian Nuclear Receptors. Chem. Rev. 114, 233–254 (2014). 7. Rastinejad, F., Huang, P., Chandra, V. & Khorasanizadeh, S. Understanding nuclear receptor form and function using structural biology. J. Mol. Endocrinol. 51, T1–T21 (2013). 8. Rastinejad, F., Ollendorff, V. & Polikarpov, I. Nuclear receptor full-length architectures: confronting myth and illusion with high resolution. Trends Biochem. Sci. 40, 16–24 (2015). 9. Bramlett, K. S., Yao, S. & Burris, T. P. Correlation of Farnesoid X Receptor Coactivator Recruitment and Cholesterol 7α-Hydroxylase Gene Repression by Bile Acids. Mol. Genet. Metab. 71, 609–615 (2000). 10. Savkur, R. S. et al. Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α. J. Pharmacol. Exp. Ther. 312, 170–178 (2005). 11. Chiang, J. Y. L. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J. Hepatol. 40, 539–551 (2004). 12. Claudel, T., Zollner, G., Wagner, M. & Trauner, M. Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim. Biophys. Acta BBA - Mol. Basis Dis. 1812, 867–878 (2011). 13. Xiang, D. et al. The regulation of tissue-specific farnesoid X receptor on genes and diseases involved in bile acid homeostasis. Biomed. Pharmacother. 168, 115606 (2023). 14. Goodwin, B. et al. A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis. Mol. Cell 6, 517–526 (2000). 15. Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005). 16. Ananthanarayanan, M., Balasubramanian, N., Makishima, M., Mangelsdorf, D. J. & Suchy, F. J. Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid Receptor. J. Biol. Chem. 276, 28857–28865 (2001). 17. Lee, H. et al. FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine. J. Lipid Res. 47, 201–214 (2006). 18. Poupon, R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: An overview of their mechanisms of action. Clin. Res. Hepatol. Gastroenterol. 36, S3–S12 (2012). 19. Hirschfield, G. M., Heathcote, E. J. & Gershwin, M. E. Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches. Gastroenterology 139, 1481–1496 (2010). 20. Lee, F. Y., Lee, H., Hubbert, M. L., Edwards, P. A. & Zhang, Y. FXR, a multipurpose nuclear receptor. 21. Wang, Y.-D., Chen, W.-D., Moore, D. D. & Huang, W. FXR: a metabolic regulator and cell protector. Cell Res. 18, 1087–1095 (2008). 22. Han, C. Update on FXR Biology: Promising Therapeutic Target? Int. J. Mol. Sci. 19, 2069 (2018). 23. Venetsanaki, V., Karabouta, Z. & Polyzos, S. A. Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis. Eur. J. Pharmacol. 863, 172661 (2019). 24. Modica, S. & Moschetta, A. Nuclear bile acid receptor FXR as pharmacological target: Are we there yet? FEBS Lett. 580, 5492–5499 (2006). 25. Chávez-Tapia, N., Uribe, M., Ponciano-Rodríguez, G., Medina-Santillán, R. & Méndez-Sánchez, N. New insights into the pathophysiology of nonalcoholic fatty liver disease. Ann. Hepatol. 8, S9–S17 (2009). 26. Pellicciari, R. et al. 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity. J. Med. Chem. 45, 3569–3572 (2002). 27. De Marino, S., Festa, C., Sepe, V. & Zampella, A. Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists. in Bile Acids and Their Receptors (eds. Fiorucci, S. & Distrutti, E.) vol. 256 137–165 (Springer International Publishing, Cham, 2019). 28. Nevens, F. et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N. Engl. J. Med. 375, 631–643 (2016). 29. Hirschfield, G., M. et al. Efficacy of Obeticholic Acid in patients with Primary Biliary Cirrhosis and inadequate response to Ursodeoxycholic acid. Gastroenterology 148, 751-761.e8 (2015). 30. Kowdley, K. V. et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67, 1890–1902 (2018). 31. Eaton, J. E. et al. Liver Injury in Patients With Cholestatic Liver Disease Treated With Obeticholic Acid. Hepatology 71, 1511–1514 (2020). 32. U.S Food & Drug Administration. Ocaliva (obeticholic acid) by Intercept Pharmaceuticals: Drug Safety Communication - Serious Liver Injury Being Observed in Patients without Cirrhosis. https://www.fda.gov/safety/medical-product-safety-information/ocaliva-obeticholic-acid-intercept-pharmaceuticals-drug-safety-communication-serious-liver-injury (2024). 33. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. The Lancet 385, 956–965 (2015). 34. Mudaliar, S. et al. Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Gastroenterology 145, 574-582.e1 (2013). 35. Ratziu, V. et al. REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis. Contemp. Clin. Trials 84, 105803 (2019). 36. Patel, K. et al. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Hepatology 72, 58–71 (2020). 37. Xu, J. et al. IL ‐31 Levels Correlate with Pruritus in Patients with Cholestatic and Metabolic Liver Diseases and is FXR Responsive in NASH. Hepatology 77, 20–32 (2023). 38. Hazarika, S. et al. Nuclear Receptor Interdomain Communication is Mediated by the Hinge with Ligand Specificity. J. Mol. Biol. 436, 168805 (2024). 39. Maloney, P. R. et al. Identification of a Chemical Tool for the Orphan Nuclear Receptor FXR. J. Med. Chem. 43, 2971–2974 (2000). 40. Tully, D. C. et al. Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J. Med. Chem. 60, 9960–9973 (2017). 41. Wang, H. et al. A novel intestinal-restricted FXR agonist. Bioorg. Med. Chem. Lett. 27, 3386–3390 (2017). 42. Jiang, L. Farnesoid X receptor (FXR): Structures and ligands. Comput. Struct. Biotechnol. J. (2021). 43. Heering, J. et al. Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators. ACS Chem. Biol. 17, 3159–3168 (2022). 44. Downes, M. et al. A Chemical, Genetic, and Structural Analysis of the Nuclear Bile Acid Receptor FXR. Mol. Cell. 45. Zheng, W. et al. A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly. ChemBioChem 18, 721–725 (2017). 46. Weymouth-Wilson, A., Packer, G., Linclau, B., Kydd-Sinclair, D. & Watson, K., A. Fluorinated Bile Acid Derivatives. 1–107 (2020). 47. Hofmann, A. F. The Continuing Importance of Bile Acids in Liver and Intestinal Disease. Arch. Intern. Med. 159, 2647 (1999). 48. Winn, M. D. et al. Overview of the CCP 4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011). 49. Adams, P. D. et al. PHENIX : a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010). 50. Emsley, P. & Cowtan, K. Coot : model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004). 51. Chen, V. B. et al. MolProbity : all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010). 52. McNicholas, S., Potterton, E., Wilson, K. S. & Noble, M. E. M. Presenting your structures: the CCP 4 mg molecular-graphics software. Acta Crystallogr. D Biol. Crystallogr. 67, 386–394 (2011). 53. Kolberg, L. et al. g:Profiler—interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Res. 51, W207–W212 (2023). 54. Tang, D. et al. SRplot: A free online platform for data visualization and graphing. PLOS ONE 18,. 55. Shannon, P. et al. Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 13, 2498–2504 (2003). 56. Doncheva, N. T., Morris, J. H., Gorodkin, J. & Jensen, L. J. Cytoscape StringApp: Network Analysis and Visualization of Proteomics Data. J. Proteome Res. 18, 623–632 (2019). 57. Agrawal, A. et al. WikiPathways 2024: next generation pathway database. Nucleic Acids Res. 52, D679–D689 (2024). 58. Livak, K. J. & Schmittgen, T. D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods 25, 402–408 (2001). 59. Pellicciari, R. et al. Back Door Modulation of the Farnesoid X Receptor: Design, Synthesis, and Biological Evaluation of a Series of Side Chain Modified Chenodeoxycholic Acid Derivatives. J. Med. Chem. 49, 4208–4215 (2006). 60. Renaud, J. P. & Moras*, D. Structural studies on nuclear receptors: Cell. Mol. Life Sci. 57, 1748–1769 (2000). 61. Nettles, K., W. & Greene, G., L. Nuclear Receptor Ligands and Cofactor Recruitment: Is There a Coactivator ‘On Deck’? Mol. Cell 11, 850–851. 62. Chau, M. et al. Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis. Int. J. Gastroenterol. 3, 4 (2019). 63. Graton, J. et al. An unexpected and significantly lower hydrogen-bond-donating capacity of fluorohydrins compared to nonfluorinated alcohols. Angew. Chem. - Int. Ed. 51, 6176–6180 (2012). 64. Meyer, U., Costantino, G., Macchiarulo, A. & Pellicciari, R. Is Antagonism of E / Z -Guggulsterone at the Farnesoid X Receptor Mediated by a Noncanonical Binding Site? A Molecular Modeling Study. J. Med. Chem. 48, 6948–6955 (2005). 65. Rastinejad, F. Allosteric communications between domains of nuclear receptors. Steroids 214, 109551 (2025). 66. Rastinejad, F. The protein architecture and allosteric landscape of HNF4α. Front. Endocrinol. 14, 1219092 (2023). 67. Chandra, V. et al. The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission. Nat. Commun. 8, 868 (2017). 68. Sheng, Y. et al. Structural basis for the asymmetric binding of coactivator SRC1 to FXR-RXRα and allosteric communication within the complex. Commun. Biol. 8, 425 (2025). 69. Ozers, M. S. et al. Analysis of Ligand-Dependent Recruitment of Coactivator Peptides to Estrogen Receptor Using Fluorescence Polarization. Mol. Endocrinol. 19, 25–34 (2005). 70. Thomas, A. M. et al. Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine. Hepatology 51, 1410–1419 (2010). 71. Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism. Hepatology 68, 1574–1588 (2018). 72. Hassan, H. et al. Regulation of Chromatin Accessibility by the Farnesoid X Receptor Is Essential for Circadian and Bile Acid Homeostasis In Vivo. Cancers Basel 14, 6191 (2022). 73. Pei, J., Pan, X., Wei, G. & Hua, Y. Research progress of glutathione peroxidase family (GPX) in redoxidation. Front. Pharmacol. 14, (2023). 74. Li, R., Jia, Z. & Zhu, H. Regulation of Nrf2 Signaling. React. Oxyg. Species Apex 8, 312–322 (2019). 75. Wu, H., Liu, G., He, Y., Da, J. & Xie. Obeticholic acid protects against diabetic cardiomyopathy by activation of FXR/Nrf2 signaling in db/db mice. Eur. J. Pharmacol. 5, (2019). 76. Liu, J. et al. NRF2 and FXR dual signaling pathways cooperatively regulate the effects of oleanolic acid on cholestatic liver injury. Phytomedicine 108, (2023). 77. Wigger, L. et al. System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLOS ONE 14, (2019). 78. You, W. et al. Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1. Sci. Rep. 7, 591 (2017). 79. Feng, Q. et al. Activation of FXR Suppresses Esophageal Squamous Cell Carcinoma Through Antagonizing ERK1/2 Signaling Pathway. Cancer Manag. Res. 13, 5907–5918 (2021). 80. Jiang, Y. et al. Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57, 1098–1106 (2013).