{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Caspase‐14 is a unique, non‐apoptotic caspase that is almost exclusively expressed in differentiated keratinocytes of the suprabasal epidermis and hair follicles. It is activated during terminal differentiation and cornification, where its proteolytic activity is essential for processing profilaggrin/filaggrin into free amino acids and their derivatives—the natural moisturizing factors that maintain skin hydration and effective barrier function against water loss and UV damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In developing and adult skin, caspase‐14 activity coincides with the formation of the stratum corneum, and its deficiency leads to structural abnormalities such as altered profilaggrin processing, delayed cornification, parakeratosis, and increased permeability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Its expression is modulated by various regulatory factors; for instance, the long non‐coding RNA TINCR promotes expression of several key differentiation genes including CASP14"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while vitamin D₃ enhances caspase‐14 expression in keratinocytes—a response that is counteracted by retinoic acid."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, inflammatory cytokines, particularly those associated with a T_H2 response, can downregulate caspase‐14, thus linking its expression to skin inflammatory conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Uniquely, its activation involves atypical processing at cleavage sites distinct from other caspases"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and proper regulation of caspase‐14—also subject to inhibition by endogenous protease inhibitors such as LEKTI—is critical for maintaining normal epidermal barrier structure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Geertrui Denecker, Esther Hoste, Barbara Gilbert, et al. 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