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The Skin Barrier: A System Driven by Phase Separation.

Fengjiao Yu1, Lu Leng1, Haowen Wang1

  • 1College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China.

Cells
|September 26, 2025
PubMed
Summary
This summary is machine-generated.

Skin barrier formation is orchestrated by liquid-liquid phase separation (LLPS), creating structural and signaling condensates. This process is crucial for skin health and understanding diseases like atopic dermatitis.

Keywords:
Hippo pathwayRIPK4atopic dermatitiscorneoptosisfilaggrinkeratohyalin granulesliquid–liquid phase separationskin barrier

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Area of Science:

  • Cell Biology
  • Biophysics
  • Dermatology

Background:

  • The mammalian epidermis provides a vital barrier against environmental factors and dehydration.
  • The traditional "bricks and mortar" model explains stratum corneum formation, but recent findings highlight intracellular liquid-liquid phase separation (LLPS) as a dynamic mechanism.
  • The granular layer's lifecycle and keratinocyte terminal differentiation are key to skin barrier function.

Purpose of the Study:

  • To propose that the granular layer lifecycle is governed by LLPS.
  • To synthesize evidence supporting LLPS in keratohyalin granule (KG) formation and function.
  • To reframe skin barrier diseases as disorders of aberrant phase behavior.

Main Methods:

  • Review and synthesis of existing literature on LLPS in skin biology.
  • Analysis of the role of filaggrin (FLG) and RIPK4 in condensate formation.
  • Reinterpretation of genetic skin diseases through the lens of aberrant biomolecular condensate behavior.

Main Results:

  • Keratohyalin granules (KGs) are identified as biomolecular condensates formed by filaggrin (FLG) phase separation.
  • LLPS orchestrates KG assembly, maturation, and dissolution, driving keratinocyte flattening (corneoptosis).
  • A RIPK4-mediated LLPS pathway activates the Hippo pathway, promoting differentiation and skin barrier formation.

Conclusions:

  • LLPS is a fundamental mechanism driving both structural and signaling processes in skin barrier formation.
  • Aberrant phase behavior in biomolecular condensates underlies diseases such as atopic dermatitis, ichthyosis vulgaris, and Bartsocas-Papas syndrome.
  • This framework offers new insights into skin biology and potential therapeutic targets through biophysics-informed design.