NR1H4 nuclear receptor subfamily 1 group H member 4
ENSG00000012504 · protein coding · Open Targets profile
Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12554753, PubMed:12660231, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP- mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans- repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- PROTAC
- UniProt Ubiquitination, Small Molecule Binder
gnomAD loss of function constraint: o/e 0.39302998781204224 (upper bound 0.5568299889564514). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 88 registry trials, updated in the last three years, of the most advanced drugs against NR1H4 (ursodiol, chenodiol, cilofexor, PX-102, tropifexor, nidufexor, TERN-101), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Kui LiuShenzhen HighTide Biopharmaceutical Ltd. · 4 of 4 trials Phase 2+
- Lynda SzczechIntercept Pharmaceuticals, Inc. · 2 of 2 trials Phase 2+
- Ying HanThe First Affiliated Hospital of Air Force Medical University · 2 of 2 trials Phase 2+
- Andre BelousKowa Pharma Development Co. · 1 of 1 trials Phase 2+
- Andrew MasonUniversity of Alberta · 1 of 1 trials Phase 2+
- Caroline OvadiaKing's College London · 1 of 1 trials Phase 2+
- Christophe CorpechotAssistance Publique - Hôpitaux de Paris · 1 of 1 trials Phase 2+
- Craig McDonaldUniversity of California, Davis · 1 of 1 trials Phase 2+
- Dalia Salah SeifAssociate Professor of Physical Medicine, Rheumatology and Rehabilitation Faculty of Medicine, Menoufyia University · 1 of 1 trials Phase 2+
- David A ShapiroIntercept Pharmaceuticals - Chief Medical Officer · 1 of 1 trials Phase 2+
- Dina K. Abou El FadlFuture University in Egypt · 1 of 1 trials Phase 2+
- DoJoong ParkSeoul National University Hospital · 1 of 1 trials Phase 2+
- Ehab R. BendasFuture University in Egypt · 1 of 1 trials Phase 2+
- Enass Yousef OsmanLecturer of Pharmacology and toxicology, Faculty of Pharmacy, Tanta University · 1 of 1 trials Phase 2+
- Enrique De MadariaAlicante General University Hospital · 1 of 1 trials Phase 2+
Registry trials of ursodiol, chenodiol, cilofexor, PX-102, tropifexor, nidufexor, TERN-101 updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 69 of 82 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 6 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
39 trials of drugs against NR1H4 were stopped early; 6 give no reason
Terminated, withdrawn and suspended interventional trials of ursodiol, chenodiol, cilofexor, PX-102, tropifexor, nidufexor, TERN-101, turofexorate isopropyl, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 39.
- terminated · 2026-10-28 · King's College London · matched by the registry's drug synonyms“CTIMP randomised part of the study was halted early due to difficulty to recruit sufficient participants.”
- withdrawn · 2026-10-09 · University of Alabama at Birmingham · matched by the registry's drug synonyms“The study was terminated due to additional regulatory requirements that could not be completed within the established academic timeline. As a result, continuation of the study was not feasible.”
- withdrawn · 2026-08-12 · HighTide Therapeutics (Hong Kong) Limited · matched by the registry's drug synonyms“Corporate decision”
- terminated · 2026-08-06 · Chang Gung Memorial Hospital · matched by the registry's drug synonyms“Slow recruitment and exhaustion of available study funding.”
- terminated · 2026-07-16 · Intercept Pharmaceuticals · matched by the registry's drug synonyms“Intercept made a business decision to terminate the study based on FDA's request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.”
- terminated · 2026-06-08 · Intercept Pharmaceuticals · matched by the registry's drug synonyms“Intercept made a business decision to terminate the study based on FDA's request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.”
- terminated · 2026-03-11 · Stanford University · ursodiol (ursodeoxycholic acid, UDCA)“Lack of recruitment and funding.”
- terminated · 2025-02-25 · Gilead Sciences · matched by the registry's drug synonyms“Study stopped early after review of safety and efficacy demonstrated efficacy proof-of-concept and need for dose reduction.”
- terminated · 2025-01-28 · Novartis Pharmaceuticals · Tropifexor“The sponsor made a business decision to stop development of the trial drugs. The decision to stop the trial early was not because of any safety concerns.”
- withdrawn · 2024-11-18 · Leadiant Biosciences, Inc. · matched by the registry's drug synonyms“Lack of feasibility”
- terminated · 2024-04-09 · Nottingham University Hospitals NHS Trust · matched by the registry's drug synonyms“Slow recruitment”
- terminated · 2024-02-06 · Intercept Pharmaceuticals · matched by the registry's drug synonyms“Study stopped by sponsor due to administrative reasons”
- terminated · 2023-11-29 · Gilead Sciences · Cilofexor“Following recommendation of the external Data Monitoring Committee, after it reviewed the results of a planned interim futility analysis.”
- terminated · 2023-08-21 · Novartis Pharmaceuticals · Tropifexor“Sponsor Decision”
- terminated · 2023-07-27 · Gilead Sciences · Cilofexor“The study enrollment was terminated early by the sponsor due to recruitment challenges.”
- terminated · 2023-06-07 · Ethan Weinberg · matched by the registry's drug synonyms“Inability to adequately recruit subjects in COVID-19 pandemic”
- withdrawn · 2023-02-09 · Children's Hospital of Fudan University · matched by the registry's drug synonyms“lack of funding”
- withdrawn · 2021-09-17 · Beijing 302 Hospital · matched by the registry's drug synonyms“No participants enrolled”
- terminated · 2021-09-05 · Novartis Pharmaceuticals · Tropifexor (LJN452)No reason given
- terminated · 2021-05-03 · National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) · matched by the registry's drug synonyms“DSMB reviewed interim analysis and terminated the study due to futility.”
- terminated · 2021-04-20 · Vanderbilt University Medical Center · matched by the registry's drug synonyms“Difficulty in participant recruitment”
- suspended · 2021-04-19 · Asan Medical Center · matched by the registry's drug synonyms“Closure of main community treatment center”
- terminated · 2021-03-24 · Boston University · matched by the registry's drug synonyms“The study was halted due to low enrollment exacerbated by COVID-19.”
- terminated · 2020-09-22 · Gilead Sciences · Cilofexor, Placebo to match cilofexor“The study was terminated because of the availability of alternate therapies for primary biliary cholangitis (PBC).”
- terminated · 2020-01-28 · Dr. Falk Pharma GmbH · matched by the registry's drug synonyms“Study stopped based on the recommendation of the IDMC after a planned Interim Analysis”
Paediatric incentives and obligations for NR1H4's drugs
For ursodiol, chenodiol, cilofexor, PX-102, tropifexor, nidufexor, TERN-101, turofexorate isopropyl: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · NR1H4 is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-002828-PIP01-20 (firsocostat;cilofexor, Treatment of metabolic dysfunction-associated steatohepatitis): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 16 May 2025; EMEA-002828-PIP01-20 (firsocostat;cilofexor, Treatment of metabolic dysfunction-associated steatohepatitis): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 16 May 2025; EMEA-002554-PIP02-19 (cilofexor, Treatment of primary sclerosing cholangitis): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 12 Aug 2020; EMEA-002471-PIP01-18 (tropifexor, Treatment of non-alcoholic steatohepatitis (NASH)): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 16 Jul 2019Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: no · No EU orphan designation names ursodiol, chenodiol, cilofexor, px-102, tropifexor, nidufexor, tern-101, turofexorate isopropylRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
- Authorised in the EU: no · EMA lists no centrally authorised medicine of ursodiol, chenodiol, cilofexor, px-102, tropifexor, nidufexor, tern-101, turofexorate isopropylRule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA data download (dated snapshot), 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: no · FDA's table lists no pediatric approval of ursodiol, chenodiol, cilofexor, px-102, tropifexor, nidufexor, tern-101, turofexorate isopropylRule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-12
- Registered studies open to children: yes · 38 interventional studies of ursodiol, chenodiol, cilofexor, px-102, tropifexor, nidufexor, tern-101, turofexorate isopropyl include patients under 18; 3 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-12
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 9 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.