{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:34:23Z","timestamp":1790130863051,"version":"4.0.1"},"reference-count":148,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary biliary cholangitis (PBC) is a chronic, immune\u2010mediated liver disease characterised by cholestasis, progressive fibrosis and symptoms of pruritus and fatigue. Ursodeoxycholic acid (UDCA) is first\u2010line therapy; however, many patients respond inadequately or are intolerant. Peroxisome proliferator\u2010activated receptor (PPAR) agonists have emerged as second\u2010line options.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This review examines PPAR isoform (PPAR\u2010\u03b1, PPAR\u2010\u03b4 and PPAR\u2010\u03b3) mediated pathways relevant to PBC, and structural, biochemical and clinical efficacy and safety features of PPAR agonists for PBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Preclinical studies on therapeutic PPAR agonism and clinical literature on PPAR agonists in PBC were identified through targeted PubMed searches and manual reference screening.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PPAR\u2010\u03b1 and PPAR\u2010\u03b4 agonism improve cholestasis by reducing bile acid synthesis and inflammation. PPAR\u2010\u03b1 agonism also enhances bile acid detoxification and transport, while PPAR\u2010\u03b4 agonism improves cholestatic pruritus by reducing pruritogenic signals. Individual PPAR isoforms are also associated with different safety profiles, with PPAR\u2010\u03b1 agonism linked to hepatic and muscle signals, and PPAR\u2010\u03b3 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\u2010\u03b1 predominant agonists (off\u2010label fibrates, elafibranor) have a potential anti\u2010pruritic effect, while selective PPAR\u2010\u03b4 agonist, seladelpar, has demonstrated statistically significant improvements in pruritus. Fatigue is likely multifactorial, mediated through central nervous system effects and sleep disturbance; PPAR\u2010\u03b1 and PPAR\u2010\u03b4 agents offer possible benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Isoform selectivity contributes to the efficacy and safety profiles of PPAR agonists. Future research should investigate isoform\u2010specific mechanisms, particularly regarding symptom relief and agent\u2010 and class\u2010related toxicities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apt.70598","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T06:56:46Z","timestamp":1774853806000},"page":"1215-1235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Review Article: Targeting Peroxisome Proliferator\u2010Activated Receptors in Primary Biliary Cholangitis"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4224-4703","authenticated-orcid":false,"given":"J\u00f6rn M.","family":"Schattenberg","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II Saarland University Medical Center  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5224-2373","authenticated-orcid":false,"given":"Jesus M.","family":"Banales","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases Biogipuzkoa Health Research Institute, Donostia University Hospital  San Sebastian Spain"},{"name":"Department of Biochemistry and Genetics, School of Sciences University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Hirschfield","sequence":"additional","affiliation":[{"name":"The Autoimmune and Rare Liver Disease Programme, Division of Gastroenterology and Hepatology, Toronto General Hospital Toronto  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4009-8087","authenticated-orcid":false,"given":"Palak","family":"Trivedi","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy University of Birmingham  Birmingham UK"},{"name":"Liver Unit University Hospitals Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward E.","family":"Cable","sequence":"additional","affiliation":[{"name":"CymaBay Therapeutics  Fremont California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"McWherter","sequence":"additional","affiliation":[{"name":"CymaBay Therapeutics  Fremont California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Billin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria B.","family":"Crittenden","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.  Foster City California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Budas","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.  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