Psoriasis Up Close: A Metabolic Border-Zone Model of Disease Pathogenesis and Treatment

Psoriasis is traditionally defined and treated as a chronic inflammatory immune-mediated disease. In this manuscript, we propose an alternative, integrative model in which psoriasis isprimarily a disorder of surface and border tissues driven by disturbed cellular metabolism,with inflammation representing a secondary phenomenon. Psoriasis predominantly manifestsin anatomical border zones, such as skin folds, hairlines, nail beds, and joint surfaces,wherecells depend critically on diffusion- and osmosis-based metabolic processes. These vulnerableregions are highly sensitive to alterations in microcirculation, oxygen delivery, nutrientavailability, and blood composition.We argue that a range of comorbidities and risk factors, including thyroid dysfunction,obesity, hyperhomocysteinemia, smoking, nutritional deficiencies (notably vitamin D and zinc), stress-related vasospasm, and dietary imbalances, may impair mitochondrial aerobicmetabolism in these border cells. This metabolic disruption promotes a shift from aerobicrespiration to anaerobic glycolysis, leading to the accumulation of mitochondrial wasteproducts and crystalline debris, particularly in confined tissue spaces such as joints. We hypothesize that this metabolic debris acts as the primary trigger for the characteristicinflammatory response observed in psoriasis.The dual metabolic and clinical efficacy of fumarates provides key support for this model, asthese agents both restore mitochondrial metabolic balance and alleviate psoriatic inflammation. This observation suggests that inflammation is a downstream consequence ofmetabolic failure rather than the initiating cause of disease. Based on this framework, wepropose that therapeutic strategies should prioritize correction of metabolic dysfunction and associated comorbidities, after which inflammatory manifestations are expected to diminish. Such an approach may not only improve cutaneous and articular symptoms but also reduce psychological burden and social stigma associated with psoriasis.