Peroxisome Proliferator-Activated Receptors (PPARs) in Psoriasis: Metabolic Intersections, Molecular Mechanisms, and Potential Treatments

Psoriasis is a chronic, systemic inflammatory disease characterized by combined epidermal and immunological pathology. It is becoming recognized as a metabolic inflammatory disorder caused by interleukin (IL)-23/Th17 axis imbalance and lipid metabolism dysfunction. Peroxisome proliferator-activated receptors (PPARs), including peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), and peroxisome proliferator-activated receptor gamma (PPARγ), regulate metabolic homeostasis and immune tolerance, making them potential targets for treating the psoriatic march of comorbidities such as obesity, insulin resistance, psoriatic arthritis, non-alcoholic fatty liver disease, and accelerated atherosclerosis. This review aims to summarize current evidence on PPAR isoform-specific roles in psoriatic pathogenesis, explore the molecular mechanisms that link PPARs to cutaneous and systemic inflammation, and assess the therapeutic potential and translational challenges of PPAR-directed pharmacotherapy. Peer-reviewed research on PPAR biology in psoriasis, metabolic comorbidities, and the clinical effectiveness of PPAR ligands was identified by a comprehensive literature search of PubMed/MEDLINE, Scopus, and Web of Science (2014-2024, with seminal papers from 2000+). Real-world evidence, randomized controlled trials, and mechanistic studies were given priority in the analysis. In psoriatic lesions, PPARγ is downregulated, leading to nuclear factor-κB and signal transducer and activator of transcription 3 deregulation. This promotes keratinocyte hyperproliferation and Th17 cell differentiation. PPARβ/δ is overexpressed, leading to anaerobic glycolysis and peroxisomal fatty acid β-oxidation. This depletes structural barrier lipids and maintains hyperplasia. Reduced PPARα inhibits lipogenesis at the epidermal barrier. Thiazolidinedione agonists (pioglitazone, rosiglitazone) have modest but clinically significant anti-psoriatic efficacy when combined with traditional systemic medicines, resulting in cardiometabolic benefits. Preclinical studies suggest that PPAR-selective antagonists, such as 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl] sulfonyl} ethyl)benzamide 3 (GSK3787) for PPARδ, outperform broad agonism. Topical PPAR ligand bioavailability remains inadequate, necessitating innovative delivery strategies. Although PPAR modulation offers a dual-benefit treatment approach that simultaneously suppresses metabolic dysregulation and cutaneous inflammation, there are still significant gaps between genetic potential and clinical reality. Future directions include patient biomarker stratification, dual/selective agonists (glitazars), and sensible combination with biologics that target tumor necrosis factor-alpha/IL-17/IL-23. This review reframes PPARs as key players in the relationship between psoriasis and metabolic syndrome by synthesizing molecular understanding and clinical data.