Molecular Mechanisms of Skin Barrier Dysfunction and Targeted Repair Strategies: Evidence Evaluation from Basic Mechanisms to Clinical Translation

Abstract

The skin barrier is composed of stratum corneum keratinocytes and their surrounding lipid matrix, epidermal cell junctions, keratinization differentiation programs, protease regulation, and the skin surface microenvironment. Barrier abnormalities can increase transepidermal water loss and enhance skin susceptibility to irritants, allergens, and microbial-related factors; inflammation, in turn, can affect keratinocyte differentiation and lipid metabolism. This article reviews the molecular basis of barrier homeostasis focusing on filaggrin (FLG), tight junctions, stratum corneum lipids, lamellar bodies and lipid transport, skin pH, and protease regulation, and discusses intervention directions including basic moisturization, inflammation control, nuclear receptor signaling, and the microbiome. This article distinguishes between measures supported by human clinical research and guidelines, evidence from cellular/animal mechanisms, and research hypotheses yet to be verified. Existing evidence supports gentle care and regular moisturization as the basis for barrier management; if inflammatory diseases such as atopic dermatitis are present, evidence-based anti-inflammatory treatment should be adopted according to disease severity. The biological plausibility of a single molecular pathway cannot be directly equated with clinical efficacy.