The Skin Barrier: A System Driven by Phase Separation

The mammalian epidermis forms a critical barrier against environmental insults and water loss. The formation of its outermost layer, the stratum corneum, involves a rapid terminal differentiation process that has traditionally been explained by the "bricks and mortar" model. Recent advances reveal a more dynamic mechanism governed by intra-cellular liquid-liquid phase separation (LLPS). This review proposes that the lifecycle of the granular layer is orchestrated by LLPS. We synthesize evidence that keratohyalin granules (KGs) are biomolecular condensates formed by the phase separation of the in-trinsically disordered protein filaggrin (FLG). The assembly, maturation, and pH-triggered dissolution of these condensates are essential for cytoplasmic remodeling and the pro-grammed flattening of keratinocytes, a process known as corneoptosis. In parallel, we de-scribe an LLPS-based signaling pathway in which the kinase RIPK4 forms condensates that activate the Hippo pathway, promoting transcriptional reprogramming and differen-tiation. Together, these structural and signaling condensates drive skin barrier formation. We further reinterpret atopic dermatitis, ichthyosis vulgaris, and Bartsocas-Papas syn-drome as diseases of aberrant phase behavior, in which pathogenic mutations alter con-densate formation or material properties. This integrative framework offers new insight into skin biology and suggests novel opportunities for therapeutic intervention through biophysics-informed biomaterial and regenerative design.