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

Abstract

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 pruri togenic 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 pre dominant 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 inves tigate isoform- specific mechanisms, particularly regarding symptom relief and agent- and class- related toxicities.