Yu Fengjiao, Leng Lu, Wang Haowen, Du Mengmeng, Wang Liang, Xu Wenhua
College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China.
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
Cells. 2025 Sep 15;14(18):1438. doi: 10.3390/cells14181438.
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 intracellular liquid-liquid phase separation (LLPS). This review proposes that the lifecycle of the granular layer is orchestrated by LLPS. Evidence is synthesized showing that keratohyalin granules (KGs) are biomolecular condensates formed by the phase separation of the intrinsically disordered protein filaggrin (FLG). The assembly, maturation, and pH-triggered dissolution of these condensates are essential for cytoplasmic remodeling and the programmed flattening of keratinocytes, a process known as corneoptosis. In parallel, an LLPS-based signaling pathway is described in which the kinase RIPK4 forms condensates that activate the Hippo pathway, promoting transcriptional reprogramming and differentiation. Together, these structural and signaling condensates drive skin barrier formation. This review further reinterprets atopic dermatitis, ichthyosis vulgaris, and Bartsocas-Papas syndrome as diseases of aberrant phase behavior, in which pathogenic mutations alter condensate 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.
哺乳动物的表皮形成了抵御环境侵害和水分流失的关键屏障。其最外层角质层的形成涉及一个快速的终末分化过程，传统上这一过程是由“砖块与灰浆”模型来解释的。最近的进展揭示了一种由细胞内液-液相分离（LLPS）调控的更为动态的机制。本综述提出颗粒层的生命周期是由LLPS精心编排的。综合证据表明，角蛋白透明颗粒（KGs）是由内在无序蛋白丝聚合蛋白（FLG）相分离形成的生物分子凝聚物。这些凝聚物的组装、成熟以及pH触发的溶解对于细胞质重塑和角质形成细胞的程序性扁平化（称为角质形成细胞凋亡）至关重要。同时，还描述了一条基于LLPS的信号通路，其中激酶RIPK4形成凝聚物，激活Hippo通路，促进转录重编程和分化。这些结构和信号凝聚物共同驱动皮肤屏障的形成。本综述进一步将特应性皮炎、寻常型鱼鳞病和巴托卡斯-帕帕斯综合征重新解释为异常相行为疾病，其中致病突变会改变凝聚物的形成或物质特性。这个综合框架为皮肤生物学提供了新的见解，并通过基于生物物理学的生物材料和再生设计为治疗干预提出了新的机会。
