PPAR Pathways Link Psoriasis Inflammation With Metabolic Comorbidities, Review Finds
Peroxisome proliferator-activated receptors (PPARs) may represent a key mechanistic bridge between cutaneous inflammation and metabolic dysfunction in psoriasis, according to a comprehensive review examining molecular pathways and therapeutic implications. The findings position PPAR signaling as a potential target for addressing both skin disease and systemic comorbidities.
Psoriasis is increasingly recognized as a metabolic inflammatory disorder driven by imbalance in the IL-23/Th17 axis and disruptions in lipid metabolism. The review highlights how PPAR isoforms—PPARα, PPARβ/δ, and PPARγ—regulate immune responses and metabolic homeostasis. Dysregulation of these pathways appears to contribute to both epidermal pathology and systemic disease.
In psoriatic lesions, PPARγ is downregulated, leading to activation of inflammatory signaling pathways such as nuclear factor-κB and STAT3, which promote keratinocyte proliferation and Th17 differentiation. In contrast, PPARβ/δ is overexpressed, driving metabolic shifts that deplete barrier lipids and sustain epidermal hyperplasia. Reduced PPARα further impairs lipid synthesis at the skin barrier.
The authors describe psoriasis as “a metabolic inflammatory disorder caused by IL-23/Th17 axis imbalance and lipid metabolism dysfunction,” and note that PPARs “regulate metabolic homeostasis and immune tolerance,” making them relevant therapeutic targets.
Clinical data on PPAR-directed therapies remain limited but suggest potential benefit. Thiazolidinedione agonists such as pioglitazone have demonstrated modest improvement in psoriasis when used with conventional systemic therapies, alongside cardiometabolic benefits. Preclinical studies indicate that selective targeting of PPAR pathways may yield stronger anti-inflammatory effects than broader activation strategies.
Despite this promise, translational challenges persist. Topical delivery remains limited by poor bioavailability, and further work is needed to identify patient subsets most likely to benefit. The authors emphasize that “PPAR modulation offers a dual-benefit treatment approach” but acknowledge that gaps remain between mechanistic understanding and clinical application.
Reference
Pinnelli VBK, T SB, Ca J, et al. Peroxisome proliferator-activated receptors (ppars) in psoriasis: metabolic intersections, molecular mechanisms, and potential treatments. Cureus. Published online March 2, 2026. doi:10.7759/cureus.104583
