Rewiring the psoriasis-metabolism axis: therapeutic potential of saroglitazar beyond PPAR modulation

Psoriasis (PSO) is a chronic, immune-mediated inflammatory disorder that affects approximately 2-3% of the global population, or over 100 million individuals worldwide. Far beyond its cutaneous manifestations, PSO is now recognized as a systemic inflammatory condition tightly intertwined with metabolic syndrome, insulin resistance, and heightened cardiovascular risk. Clinical and epidemiological data reveal its strong association with type 2 diabetes, hypertension, dyslipidemia, hepatic steatosis, and non-alcoholic fatty liver disease, collectively amplifying its systemic burden. At the molecular level, these comorbidities converge on dysregulated signaling cascades, including NF-κB, MAPK, and STAT3, that sustain the chronic pro-inflammatory state. Saroglitazar (SGZ), initially developed as a dual PPAR-α/γ agonist for diabetic dyslipidemia, is indeed emerging as a promising multi-targeted therapy with pleiotropic effects. Current evidence supports its role as a system-level modulator that fine-tunes insulin signaling, reduces oxidative stress, suppresses neuroinflammation, and modulates key inflammatory pathways such as NF-κB, MAPK, and STAT3, aligning well with its broadened therapeutic potential beyond diabetes management. To our knowledge, this is the first comprehensive synthesis to unravel SGZ's mechanistic intersections across metabolic and inflammatory axes and map its clinical relevance to psoriasis. By bridging the dermatological landscape with metabolic comorbidity management and lifestyle interventions, SGZ-proposed mechanisms in the skin, however, have not yet been thoroughly investigated with direct preclinical and clinical evidence in psoriasis and are still hypothesis-generating.