When and How Ferroptosis Becomes Pathogenetic in Psoriasis

Psoriasis is classically framed as an IL-23/IL-17/TNF-driven immune disease, yet durable remission remains elusive for many patients, suggesting that epidermal-intrinsic pathogenic mechanisms shape chronicity and therapeutic escape. Here we propose ferroptosis, viewed as iron-dependent membrane lipid peroxidation coupled to failure of lipid repair, as a unifying, epidermis-centered axis that links metabolic stress to immune amplification in psoriasis. In this review, we synthesize experimental evidence showing that GPX4 suppression, lipid peroxidation accumulation, dysregulated iron handling and PUFA-remodeling programs, together define ferroptosis-permissive niches in psoriatic plaques. We also integrate functional studies demonstrating that ferroptosis modulation reshapes psoriasiform inflammation and discuss why ferroptotic stress can act as a feed-forward amplifier at the immune-epidermal interface, reinforcing IL-17/TNF/IFN-γ circuits and myeloid-Th17 crosstalk. Finally, we highlight ferroptosis-related transcriptomic signatures as a stratification layer that captures metabolic heterogeneity beyond cytokine profiling, with implications for relapse and incomplete response to existing therapies. The translational opportunities and constraints for ferroptosis-targeted interventions are outlined, advocating precision normalization of epidermal redox homeostasis as a new therapeutic frontier in psoriasis.