In this study, we constructed the proteomics profiles of PN EpCs and PN EpC-derived exosomes using the quantitative proteomics techniques. Our findings revealed that EpCs in PN patients exhibit abnormal morphology and biological functions, which are influenced by the high metabolic levels and activation of inflammasome pathways in the immune microenvironment. Meanwhile, the exosomes and ECMs secreted by the dysfunctional epidermal cells could further affect the immune microenvironment. This study aims to identify potential targets for disease treatment by analyzing the relationship between PN epidermal cells, extracellular vesicles, and the immune microenvironment. These results can provide guidance in the discovery of improved clinical treatments for PN.