Evolving paradigms in primary biliary cholangitis: from molecular mechanisms to personalized therapeutics with seladelpar, elafibranor, and beyond

Abstract Introduction Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. Recent advancements in our understanding of the complex interplay between genetic predisposition, environmental triggers, and immune dysregulation have led to novel therapeutic approaches. This review explored the evolving landscape of PBC management, highlighting emerging treatment paradigms and their potential to improve patient outcomes. Main body Ursodeoxycholic acid (UDCA) remains the standard of care for primary biliary cholangitis (PBC), with proven benefits for improving transplant-free survival. Nonetheless, up to 40% of the patients exhibit an incomplete response, highlighting the need for alternative therapies. Recent clinical trials have underscored the efficacy of novel targeted agents, such as seladelpar and elafibranor, both peroxisome proliferator-activated receptor (PPAR) agonists. These therapies not only improve biochemical markers, but also alleviate key symptoms, including pruritus and fatigue, thereby offering a more comprehensive approach to disease management. Advances in predictive tools, particularly the UDCA Response Score, facilitate the early identification of patients who are unlikely to respond adequately to UDCA and enable timely initiation of second-line therapies. The integration of precision-based strategies with mechanism-driven treatments represents a significant paradigm shift in PBC care. By addressing disease progression and symptom burden, PPAR agonists, along with predictive algorithms, have the potential to redefine therapeutic standards and improve long-term patient outcomes. Conclusion The treatment paradigm for primary biliary cholangitis (PBC) is shifting towards tailored approaches that integrate novel therapies targeting key pathogenic pathways. Peroxisome proliferator-activated receptor (PPAR) agonists and other emerging agents offer promising options for patients with incomplete responses to ursodeoxycholic acid (UDCA), addressing both biochemical endpoints and symptom burden. This evolving landscape underscores the need for personalized strategies based on the disease stage, symptom profile, and patient-specific factors. Future research should prioritise the validation of the long-term efficacy and safety of these therapies, refinement of diagnostic and prognostic biomarkers, and incorporation of novel agents into evidence-based treatment algorithms. A multidisciplinary, patient-centered approach is essential for optimising outcomes and improving quality of life in individuals affected by this complex autoimmune liver disease.