DeCure for Progressive familial intrahepatic cholestasis type 1
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for progressive familial intrahepatic cholestasis type 1 — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleProgressive familial intrahepatic cholestasis type 1 maps to a 5-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for progressive familial intrahepatic cholestasis type 1 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
nuclear receptor subfamily 1 group H member 4 (NR1H4) — NR1H4 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet iiidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3BEJ · 1.9 Å · ligand YTTRIUM (III) ION (YT3). Experimental structure, not a prediction.
What the evidence adds up to
Progressive familial intrahepatic cholestasis type 1 is one of several inherited disorders that impair bile flow, predominantly in children, and if untreated leads to end-stage liver disease and death. The role and timing of liver transplantation in PFIC1 specifically remains debated, though for appropriately selected patients transplantation offers an excellent survival benefit. A 1981 report of four siblings with familial intrahepatic cholestasis detected in early infancy described that the two male siblings developed biliary cirrhosis and fatal hepatocellular carcinoma, while the female siblings had persistent hepatomegaly and recurrent cholestasis without cancer. That report noted the oncogenic risk, particularly in males, had not been generally appreciated.
A 2022 review of the literature on familial intrahepatic cholestasis and hepatobiliary cancers states that mutations in FIC genes can influence serum and hepatic bile acid levels. Experimental studies on the NR1H4 gene, which encodes the farnesoid X-activated receptor involved in bile salt synthesis, have shown that high bile acid concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration — all risk conditions for hepatocellular carcinoma and cholangiocarcinoma. The review reports that HCC and CCA can emerge in patients with mutations in ABCB11, ABCB4, TJP2, and other FIC genes. A separate 2022 report characterises a novel NR1H4 mutation causing PFIC5, a rare low-γGT intrahepatic cholestasis considered when ATP8B1/FIC1 and ABCB11/BSEP mutations are absent.
A 2025 case report describes a 20-month-old girl hospitalised for acute liver failure and later diagnosed with PFIC, noting that jaundice is a fundamental clinical sign frequently overlooked beyond the strictly neonatal period, and that the case was unusual for its rarity and early onset. No abstract in this set reports any drug treatment, any clinical trial, or any quantitative survival or response rates for PFIC1. What is missing are prospective studies that stratify patients by specific genetic mutation, funding for trials of any pharmacological intervention, and long-term outcome data that distinguish PFIC1 from other PFIC subtypes after transplantation or any other management.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
World Journal of Transplantation · 2016 · 65 citations · open access
Liver transplantation and the management of progressive familial intrahepatic cholestasis in children
AbstractProgressive familial intrahepatic cholestasis (PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.
American Journal of Clinical Pathology · 1981 · 47 citations
Hepatoma in Siblings with Progressive Familial Cholestatic Cirrhosis of Childhood
AbstractThis report describes four siblings affected with familial intrahepatic cholestasis detected in early infancy. In the two male siblings, biliary cirrhosis and fatal hepatocellular carcinoma later developed, whereas the female siblings have had persistent hepatomegaly and recurrent episodes of cholestasis. Sequential biopsies show that this rare disorder of unknown etiology must be added to the many causes of giant cell transformation of the liver in infancy. Its oncogenic risk, particularly in males, has not been generally appreciated.
Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature
AbstractThe family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
AbstractThe paper describes the case of a 20-month-old girl hospitalized for acute liver failure, later diagnosed with progressive familial intrahepatic cholestasis (PFIC). Jaundice is often a fundamental clinical sign that is frequently overlooked, not only in the strictly neonatal period.The uniqueness of this case lies in the rarity and early onset of the clinical presentation of PFIC.
Zeitschrift für Gastroenterologie · 2022 · 0 citations
In vitro and in silico characterization of a novel NR1H4/FXRmutation causing Progressive Familial Intrahepatic Cholestasis Type5
AbstractBackground Mutations in NR1H4/FXR underlie Progressive Familial Intrahepatic Cholestasis Type 5 (PFIC5). FXR is a member of the nuclear receptor family that, heterodimerized with RXRα, transactivates the ABCB11/BSEP promoter. PFIC5-associated NR1H4 mutations result in reduced or absent BSEP expression. Consequently, PFIC5 is a rare, low-γGT intrahepatic cholestasis to be considered in absence of disease-causing ATP8B1/FIC1 and ABCB11/BSEP mutations. Here, we describe and characterize a novel NR1H4/FXR mutation causing PFIC5 in a patient.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
