I. Abnormalities in Skin Barrier Structure and Function

Disrupted Lipid Metabolism in the Stratum Corneum

The integrity of the lipid bilayer—composed of ceramides, free fatty acids, and cholesterol—is compromised, leading to increased transepidermal water loss (TEWL) and allowing external irritants to easily penetrate the dermis.

Deficiency of Natural Moisturizing Factors (NMF)

Insufficient levels of components such as amino acids, urea, and PCA impair the hydration capacity of the stratum corneum, keeping the skin in a state of chronic dryness and weakening its barrier repair function.

Keratinocyte Dysfunction

Reduced expression of intercellular junction proteins (e.g., desmosomes) leads to loose arrangement of stratum corneum cells and the formation of "gap channels," thereby reducing the physical barrier's defensive capability.

II. Overactivation of Immune-Inflammatory Responses

Abnormal Activation of Pattern Recognition Receptors (PRRs)

Upon recognizing external stimuli (such as bacterial lipopolysaccharides or chemical substances), TLR2/4 receptors trigger the NF-κB inflammatory pathway, leading to the release of pro-inflammatory cytokines like IL-6 and TNF-α.

Mast Cell Degranulation

Stimulation triggers the release of mediators such as histamine and tryptase, causing vasodilation and increased vascular permeability, which manifests as symptoms like redness and itching.

Th1/Th2 Immune Imbalance

In atopic sensitive skin, Th2-type cytokines (e.g., IL-4, IL-13) predominate, promoting IgE-mediated immediate hypersensitivity reactions.

III. Dysregulation of Neurovascular Control Mechanisms

Hypersensitivity of C-fiber Nerve Endings

Sensory nerve fibers release Substance P and calcitonin gene-related peptide (CGRP), inducing vasodilation and mast cell activation, thereby creating "neurogenic inflammation."

Abnormal vascular reactivity

Endothelial dysfunction leads to an imbalance in vasomotor regulation, manifesting as recurrent flushing or persistent erythema.

IV. Genetic and epigenetic factors

FLG gene mutations

Defects in the filaggrin gene impair the synthesis of stratum corneum barrier proteins; this is commonly observed in sensitive skin associated with atopic dermatitis.

Epigenetic modifications

Environmental factors (e.g., UV radiation, pollution) alter the expression of barrier-related genes (e.g., LOR, INV) through mechanisms such as DNA methylation and histone acetylation.

V. Imbalance of the skin microbiome

Reduced microbial diversity

A decline in dominant beneficial bacteria (such as *Lactobacillus*) and the overgrowth of pro-inflammatory bacteria (such as *Staphylococcus*) disrupt the immunoregulatory function of the microbial barrier.

Biofilm formation

Pathogenic bacteria adhere to the skin surface via biofilms, evade host immune surveillance, and persistently induce low-grade inflammation.

These underlying mechanisms interact to create a vicious cycle of "barrier disruption – inflammation activation – neuronal hyper-reactivity," ultimately manifesting as the clinical symptoms of sensitive skin.