Ferroptosis in skin diseases and cutaneous immunology

Ferroptosis is a regulated form of cell death driven by iron-dependent phospholipid peroxidation, but its immunological identity is not fixed. This context dependence complicates therapeutic development: ferroptosis may eliminate malignant cells but can also amplify inflammation or impair protective immune responses. Moreover, sublethal ferroptosis-associated stress can alter cellular function without causing cell death. The skin provides an informative model for investigating these divergent effects because epidermal differentiation and cutaneous compartmentalization create spatial heterogeneity in iron handling, lipid composition, and redox status. This review integrates the core molecular machinery of ferroptosis with the spatial biology and immunology of the skin. We examine ferroptotic death and sublethal stress across skin-resident and immune-cell populations, focusing on their distinct immunological consequences. Evidence from melanoma, psoriasis, vitiligo, systemic and cutaneous lupus erythematosus, ultraviolet-induced skin injury, and atopic dermatitis is evaluated with particular attention to the distinction between molecular associations, mechanistic evidence, and causal contributions to disease. Finally, we assess emerging skin-directed delivery platforms, including nanoparticles, microneedles, and extracellular vesicles, and critically compare their delivery characteristics, potential for cell-type-selective modulation, and translational readiness. Key translational challenges include in vivo stability, off-target effects, long-term safety, and manufacturing scalability. Progress toward clinical translation will require spatially resolved, cell-type-specific functional validation and more selective therapeutic strategies.