Obeticholic Acid

Overview

Obeticholic acid (OCA; INT-747) is a semi-synthetic bile acid derivative and potent agonist of the farnesoid X receptor (NR1H4 / FXR). It activates the FXR–SHP axis, suppressing STAT3 phosphorylation and downregulating BCL2L1 (Bcl-xL)-mediated survival in cholangiocytes. Approved for primary biliary cholangitis (PBC); under investigation for cholangiocarcinoma and non-alcoholic steatohepatitis.

Evidence in the corpus

• FXR agonism by obeticholic acid (OCA/INT-747) reactivates the SHP/LRH-1 pathway to suppress CCA proliferation and migration; heterogeneous FXR expression across CCA subtypes (pCCA/dCCA H-score <120) suggests DNMT-inhibitor combinations may be needed to restore FXR responsiveness before OCA can act PMID:25608663

Resistance mechanisms

• FXR downregulation via promoter methylation (low H-score in pCCA/dCCA) limits OCA efficacy; combination with DNMT inhibitors proposed to restore FXR expression PMID:25608663

Cancer types (linked)

• CHOL — cholangiocarcinoma (iCCA, pCCA, dCCA)

Sources

• PMID:25608663

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