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1. Introduction

The human skin is the largest organ of the body and serves as the primary physical barrier between internal tissues and the external environment. This barrier function is primarily executed by the stratum corneum, the outermost layer of the epidermis, which is composed of terminally differentiated keratinocytes embedded within a lipid-rich extracellular matrix. The structural and biochemical integrity of this layer is essential for the prevention of pathogen entry, the regulation of transepidermal water loss, and the modulation of immune responses.

Over the past two decades, substantial research has established that impairment of skin barrier function is not merely a consequence of dermatologic disease, but frequently a primary driver of its initiation and perpetuation. Barrier dysfunction facilitates the penetration of allergens, environmental irritants, and microorganisms into the viable epidermis, triggering sustained inflammatory cascades that underlie conditions such as atopic dermatitis (AD), psoriasis vulgaris, rosacea, and ichthyosis vulgaris (Elias and Feingold, 2006; Brune et al., 2014).

From a genetic perspective, loss-of-function mutations in the filaggrin gene (FLG) represent the most well-characterised heritable risk factor for atopic dermatitis and have been found to predispose individuals to a broader range of allergic and inflammatory skin conditions (Palmer et al., 2006; Irvine et al., 2011). Beyond genetics, environmental stressors including low humidity, detergent exposure, and ultraviolet irradiation further compromise barrier integrity through disruption of ceramide synthesis, desquamation regulation, and tight junction assembly.

Despite the broad clinical relevance of barrier dysfunction, the therapeutic literature has historically been fragmented by disease category. This review aims to consolidate current understanding of barrier pathophysiology and its clinical implications across a range of dermatologic conditions, and to evaluate therapeutic strategies with meaningful evidence of barrier restoration.

2. Structure and Function of the Skin Barrier

2.1 The Stratum Corneum

The stratum corneum (SC) is classically described by the "bricks and mortar" model, wherein corneocytes (terminally differentiated, anucleate keratinocytes) constitute the bricks, and a multilamellar lipid matrix composed of ceramides, cholesterol, and free fatty acids constitutes the mortar (Elias, 1983). This architecture provides both a physical impediment to transcutaneous penetration and a hydrophobic gradient that minimises passive water loss.

Corneocyte maturation is dependent on the expression of filaggrin, a structural protein derived from profilaggrin that facilitates the aggregation of keratin filaments within corneocytes. Filaggrin is subsequently catabolised into natural moisturising factors (NMFs), including pyrrolidone carboxylic acid and urocanic acid, which are critical for maintaining stratum corneum hydration and acidic pH (Scott et al., 1982). Disruption of this process, whether through genetic mutation or protease-mediated degradation, significantly impairs SC integrity.

2.2 Tight Junctions and the Lamellar Body Secretory System

While the SC forms the outermost barrier, tight junctions (TJs) in the stratum granulosum provide a critical secondary barrier, regulating paracellular permeability within the viable epidermis. Key components include claudin-1, claudin-4, occludin, and zonula occludens-1. Claudin-1 knockout mouse models have demonstrated that loss of this protein results in severe dehydration and neonatal death, underscoring its non-redundant role in barrier function (Furuse et al., 2002).

Lamellar bodies (LBs), also known as membrane-coating granules, are secretory organelles within stratum granulosum keratinocytes responsible for the exocytosis of lipid precursors and hydrolytic enzymes into the intercorneocyte space. Defects in LB biogenesis or exocytosis result in incomplete lipid lamella formation, directly impairing the barrier lipid matrix. Harlequin ichthyosis, a severe genodermatosis caused by mutations in ABCA12 (a lipid transporter essential for LB cargo loading), exemplifies the catastrophic consequences of this pathway failure (Kelsell et al., 2005).

2.3 The Acid Mantle and Antimicrobial Peptides

The skin surface maintains an acidic pH of approximately 4.5 to 5.5, colloquially termed the acid mantle, which serves multiple functions. Acidic conditions are required for the optimal activity of serine proteases involved in desquamation, including kallikrein-5 and kallikrein-7 (Brattsand et al., 2005). Additionally, the acidic environment inhibits the colonisation of pathogenic bact