Review Article: Targeting Peroxisome Proliferator‐Activated Receptors in Primary Biliary Cholangitis

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterised by cholestasis, progressive fibrosis and symptoms of pruritus and fatigue. Ursodeoxycholic acid (UDCA) is first-line therapy; however, many patients respond inadequately or are intolerant. Peroxisome proliferator-activated receptor (PPAR) agonists have emerged as second-line options. AIMS: This review examines PPAR isoform (PPAR-α, PPAR-δ and PPAR-γ) mediated pathways relevant to PBC, and structural, biochemical and clinical efficacy and safety features of PPAR agonists for PBC. METHODS: Preclinical studies on therapeutic PPAR agonism and clinical literature on PPAR agonists in PBC were identified through targeted PubMed searches and manual reference screening. RESULTS: PPAR-α and PPAR-δ agonism improve cholestasis by reducing bile acid synthesis and inflammation. PPAR-α agonism also enhances bile acid detoxification and transport, while PPAR-δ agonism improves cholestatic pruritus by reducing pruritogenic signals. Individual PPAR isoforms are also associated with different safety profiles, with PPAR-α agonism linked to hepatic and muscle signals, and PPAR-γ agonism associated with fluid retention/weight gain. PPAR agonists differ in isoform selectivity. Although all agonists used in PBC reduce alkaline phosphatase levels, their impact on pruritus varies; PPAR-α predominant agonists (off-label fibrates, elafibranor) have a potential anti-pruritic effect, while selective PPAR-δ agonist, seladelpar, has demonstrated statistically significant improvements in pruritus. Fatigue is likely multifactorial, mediated through central nervous system effects and sleep disturbance; PPAR-α and PPAR-δ agents offer possible benefit. CONCLUSIONS: Isoform selectivity contributes to the efficacy and safety profiles of PPAR agonists. Future research should investigate isoform-specific mechanisms, particularly regarding symptom relief and agent- and class-related toxicities.