Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Chronic Liver Diseases: Translating Mechanistic...

Peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) are ligand-activated nuclear transcription factors that orchestrate key metabolic and immuno-inflammatory networks governing hepatic homeostasis. By regulating fatty acid oxidation, insulin signaling, bile acid metabolism, and hepatic stellate cell activation, PPARs integrate metabolic and inflammatory cues central to the pathogenesis of chronic liver disorders. Chronic liver diseases (CLDs) constitute a major and growing global health burden. Metabolic dysfunction-associated steatotic liver disease (MASLD), now affecting up to one-third of the adult population worldwide, is closely linked to type 2 diabetes, cardiovascular disease, and major liver-related events. In parallel, chronic immune-mediated cholestatic liver diseases continue to pose important therapeutic challenges. Although ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), and several second-line therapeutic options are now available, a substantial proportion of patients exhibit an incomplete biochemical response, while effective disease-modifying therapies for primary sclerosing cholangitis (PSC) remain lacking. Across etiologies, persistent metabolic stress, immune-mediated injury, and maladaptive fibrogenesis represent convergent pathogenic pathways. In MASLD, PPAR agonists have shown promising effects on steatosis, necroinflammatory activity, and fibrosis regression in randomized clinical trials, positioning them among the most advanced pharmacological strategies currently under investigation. In cholestatic liver diseases, selective and dual PPAR agonists have demonstrated significant improvements in cholestasis, pruritus, and markers of disease activity, supporting their role as second-line or adjunctive therapy. This review critically appraises the current preclinical and clinical evidence on the role of PPARs in CLDs, delineates the underlying molecular mechanisms, and discusses future therapeutic perspectives. Although the available evidence is encouraging, most clinical studies have primarily demonstrated improvements in surrogate biochemical and histological endpoints rather than hard clinical outcomes. Ongoing phase III trials and long-term outcome studies will be essential to define the role of PPAR agonists within future therapeutic algorithms for CLDs.