Targets for Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, leading to biliary strictures, cholestasis, and ultimately cirrhosis. Understanding the molecular targets involved in PSC pathogenesis is critical for elucidating disease mechanisms, identifying therapeutic vulnerabilities, and supporting rational drug development. The most relevant targets in PSC are those directly involved in bile acid transport and homeostasis, immune cell recruitment and activation, and fibrogenic responses. Specifically, ATP-binding cassette transporters (ABCB11 and ABCB4) are essential for bile formation and secretion; their dysfunction leads to cholestasis and bile duct injury. Chemokine receptors (CCR2, CCR5) and their ligands (CCL24) mediate immune cell trafficking and inflammation within the biliary tree. Nuclear receptors (NR1H4/FXR, NR1I2/PXR, PPARA, PPARD) regulate bile acid metabolism and inflammatory responses. Thrombospondin 1 (THBS1) and Platelet Derived Growth Factor Receptor Beta (PDGFRB) are implicated in fibrogenesis and tissue remodeling. Collectively, these targets provide a mechanistic framework for PSC progression, from bile acid dysregulation to immune-mediated injury and fibrosis. Their study enables the identification of actionable pathways for therapeutic intervention, the development of targeted drugs (e.g., FXR agonists, CCR5 antagonists), and the discovery of biomarkers for disease monitoring and stratification.

Bile Acid Transport And Homeostasis

This category includes targets central to the regulation of bile acid transport and secretion, whose dysfunction is directly implicated in cholestasis and biliary injury in PSC. The ATP-binding cassette transporters ABCB11 and ABCB4 are essential for the export of bile acids and phospholipids, respectively. Impaired function leads to toxic bile composition, biliary epithelial damage, and triggers downstream inflammatory and fibrogenic responses. Nuclear receptors such as NR1H4 (FXR) and NR1I2 (PXR) are key transcriptional regulators of genes involved in bile acid synthesis, conjugation, and transport, modulating both hepatobiliary homeostasis and inflammatory signaling. These targets are fundamental to disease onset and progression, and represent validated or emerging therapeutic targets in PSC.

ATP Binding Cassette Subfamily B Member 11 (ABCB11)

ABCB11 encodes the bile salt export pump (BSEP), a canalicular membrane transporter that mediates the ATP-dependent excretion of conjugated bile acids from hepatocytes into bile. Structurally, BSEP is a member of the ABC transporter family, containing two transmembrane domains and two nucleotide-binding domains. Regulation occurs via nuclear receptors (FXR/NR1H4, PXR/NR1I2) and post-translational modifications. Mutations or downregulation of ABCB11 reduce bile acid secretion, causing intrahepatic cholestasis and promoting bile duct injury—hallmarks of PSC. Evidence for its pathogenic role includes reduced BSEP expression in PSC liver tissue and the phenotypic overlap with inherited BSEP deficiency (PFIC2). Therapeutically, FXR agonists upregulate BSEP expression and are in clinical trials for cholestatic diseases, including PSC. BSEP is also considered a potential biomarker for disease severity and progression.

ATP Binding Cassette Subfamily B Member 4 (ABCB4)

ABCB4 encodes the multidrug resistance protein 3 (MDR3), a phosphatidylcholine floppase that facilitates the secretion of phospholipids into bile. MDR3 consists of two transmembrane and two nucleotide-binding domains. Its function is tightly regulated by bile acid-activated nuclear receptors, notably FXR (NR1H4). ABCB4 deficiency results in toxic, detergent-like bile, causing cholangiocyte injury and sclerosing cholangitis. Genetic variants in ABCB4 are associated with increased risk and severity of PSC. Therapeutic strategies include FXR agonists to enhance MDR3 expression and ursodeoxycholic acid to protect cholangiocytes. MDR3 status may serve as a biomarker for disease susceptibility and progression.

Nuclear Receptor Subfamily 1 Group H Member 4 (NR1H4)

NR1H4 encodes the farnesoid X receptor (FXR), a ligand-activated nuclear receptor that senses bile acids and orchestrates the transcriptional regulation of genes involved in bile acid synthesis (CYP7A1 repression), conjugation, and transport (upregulation of BSEP/ABCB11, MDR3/ABCB4). FXR has a DNA-binding domain and ligand-binding domain, forming heterodimers with RXR. FXR activation reduces intrahepatic bile acid toxicity and suppresses pro-inflammatory signaling in the liver. Downregulation or dysfunction of FXR exacerbates cholestasis and inflammation in PSC. FXR agonists (e.g., obeticholic acid) are in clinical development for PSC, with evidence of biochemical improvement. FXR is also being explored as a biomarker and therapeutic modulator in cholestatic liver diseases.

Nuclear Receptor Subfamily 1 Group I Member 2 (NR1I2)

NR1I2 encodes the pregnane X receptor (PXR), a nuclear receptor that regulates expression of genes involved in bile acid detoxification and transport, including CYP3A4, ABCB11, and ABCB4. PXR contains DNA- and ligand-binding domains, and is activated by various xenobiotics and endogenous ligands. PXR activation mitigates bile acid-induced hepatotoxicity and modulates inflammation. Impaired PXR signaling is implicated in cholestatic injury and may contribute to PSC pathogenesis. PXR agonists are being evaluated preclinically for their ability to reduce cholestatic injury. PXR expression and activity may serve as a biomarker for disease risk and therapeutic response.

Immune Cell Recruitment And Inflammation

This category comprises targets that regulate immune cell trafficking, activation, and inflammatory signaling within the biliary tree. Chemokine receptors CCR2 and CCR5, and their ligand CCL24, are key mediators of monocyte and lymphocyte recruitment to sites of biliary injury, fueling chronic inflammation and perpetuating tissue damage in PSC. Their involvement is supported by elevated expression in PSC livers and functional studies demonstrating their role in immune cell infiltration and disease severity. These targets are under investigation as therapeutic targets for immunomodulation in PSC.

C-C Motif Chemokine Receptor 2 (CCR2)

CCR2 encodes a G-protein-coupled receptor expressed on monocytes and macrophages, mediating chemotaxis in response to CCL2 and related chemokines. Structurally, CCR2 has seven transmembrane domains and is regulated by inflammatory cytokines. In PSC, CCR2 expression is upregulated in portal tracts, promoting recruitment of pro-inflammatory monocytes to the liver and bile ducts. CCR2-driven infiltration exacerbates biliary inflammation and fibrosis. Pharmacological CCR2 antagonists (e.g., cenicriviroc, a dual CCR2/CCR5 inhibitor) are in clinical trials for fibrotic liver diseases, including PSC. CCR2 is also being evaluated as a biomarker for inflammatory activity and progression.

C-C Motif Chemokine Receptor 5 (CCR5)

CCR5 encodes a chemokine receptor expressed on T cells, NK cells, and monocytes, mediating migration in response to CCL3, CCL4, and CCL5. Like CCR2, CCR5 is a seven-transmembrane GPCR. In PSC, CCR5 is upregulated in inflammatory infiltrates and contributes to immune cell accumulation and chronic inflammation. Genetic polymorphisms in CCR5 have been linked to PSC susceptibility. Therapeutically, CCR5 antagonists (e.g., maraviroc, cenicriviroc) are being tested for their ability to attenuate hepatic inflammation and fibrosis. CCR5 expression may serve as a biomarker for disease activity.

C-C Motif Chemokine Ligand 24 (CCL24)

CCL24 encodes eotaxin-2, a chemokine that binds to CCR3 and, to a lesser extent, CCR2, promoting eosinophil and monocyte recruitment. Structurally, CCL24 is a small secreted protein with a conserved chemokine fold. Elevated CCL24 levels have been observed in PSC livers, correlating with inflammatory cell infiltration and fibrosis. CCL24-mediated recruitment of immune cells amplifies biliary inflammation. Antagonists of CCL24 or its receptors are being explored for their anti-inflammatory and anti-fibrotic potential in cholestatic liver diseases.

Fibrosis And Tissue Remodeling

This category includes targets that drive fibrogenesis and tissue remodeling in PSC. Platelet Derived Growth Factor Receptor Beta (PDGFRB) and Thrombospondin 1 (THBS1) are central to the activation and proliferation of hepatic stellate cells and portal fibroblasts, leading to extracellular matrix deposition and progression to cirrhosis. Their expression is increased in PSC fibrotic lesions and correlates with disease severity. Targeting these pathways holds promise for anti-fibrotic therapy in PSC.

Platelet Derived Growth Factor Receptor Beta (PDGFRB)

PDGFRB encodes a receptor tyrosine kinase that binds PDGF-BB and related ligands, activating downstream signaling cascades (PI3K/AKT, MAPK) that drive proliferation and activation of hepatic stellate cells and portal fibroblasts. Structurally, PDGFRB features an extracellular ligand-binding domain, a single transmembrane helix, and intracellular tyrosine kinase domains. In PSC, PDGFRB is upregulated in fibrotic septa and contributes to progressive fibrosis. Inhibitors of PDGFRB (e.g., imatinib, sorafenib) have shown anti-fibrotic effects in preclinical models. PDGFRB is being investigated as a therapeutic target and biomarker for advanced PSC.

Thrombospondin 1 (THBS1)

THBS1 encodes a large extracellular matrix glycoprotein involved in cell-matrix interactions, TGF-β activation, and regulation of angiogenesis. Structurally, THBS1 contains multiple domains (TSR, EGF-like, calcium-binding, and lectin domains). In PSC, THBS1 is upregulated in fibrotic areas and promotes TGF-β activation, leading to increased collagen deposition and fibrosis. Targeting THBS1 or its downstream effectors (e.g., TGF-β signaling) is a potential anti-fibrotic strategy. THBS1 is also being evaluated as a biomarker of fibrogenic activity in PSC.