Keratinocyte necroptosis in inflammatory skin diseases and acute epidermal injury: mechanisms, evidence, and therapeutic implications

The skin functions as a barrier against external insults and as an active immune organ. Keratinocytes are central to both roles, maintaining epidermal integrity while coordinating cutaneous immune responses. Necroptosis is a lytic form of regulated cell death that can compromise the epidermal barrier and release damage-associated molecular patterns, thereby linking tissue injury to immune activation. Accumulating evidence implicates keratinocyte necroptosis in multiple inflammatory skin diseases and acute epidermal injuries. This mini review summarizes the molecular regulation of keratinocyte necroptosis, critically appraises evidence for its involvement across distinct pathological contexts, and evaluates therapeutic strategies and associated translational challenges. Mechanistic studies and preliminary translational evidence suggest that necroptosis-related signaling in keratinocytes may represent a therapeutic target. However, the effects of pathway modulation may vary across disease contexts and depend on infection status and the immune microenvironment. Defining the disease-specific contribution of keratinocyte necroptosis and the corresponding therapeutic windows will therefore be essential for evaluating the clinical feasibility of this strategy.