{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Filaggrin (FLG) is a pivotal epidermal protein that serves as a master regulator of terminal keratinocyte differentiation and skin barrier formation. Initially synthesized as a large polyprotein (profilaggrin), it undergoes proteolytic processing to yield filaggrin monomers that facilitate the aggregation of keratin filaments and promote proper cornified envelope assembly (a process essential for the structural integrity of the stratum corneum)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Moreover, the degradation of filaggrin generates a range of natural moisturizing factors (NMFs) – including pyrrolidone carboxylic acid and urocanic acid – which play critical roles in maintaining stratum corneum hydration and optimal skin pH."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Loss‐of‐function mutations or acquired reduction in FLG expression result in an impaired epidermal barrier that predisposes to a spectrum of cutaneous and systemic pathologies. FLG deficiency is strongly associated with ichthyosis vulgaris and atopic dermatitis, and it serves as a major genetic risk factor for allergic sensitization, contact allergy, and asthma in the context of eczema."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Studies in both human subjects and murine models (including the flaky tail mouse) have demonstrated that the consequent barrier abnormality leads to increased transepidermal water loss, altered lipid profiles, enhanced percutaneous allergen penetration, and a dysregulated immune response that favors allergic inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Thus, FLG functions not only as a structural protein essential for proper keratinocyte maturation and the establishment of an effective barrier, but its deficiency also triggers a cascade of events that culminate in the development and persistence of atopic disease. Its central role in skin barrier integrity makes FLG and its processing pathways attractive targets for therapeutic strategies aimed at restoring barrier function and preventing allergic sensitization.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Colin N A Palmer, Alan D Irvine, Ana Terron-Kwiatkowski, et al. 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