KPRP (keratinocyte proline-rich protein) is a structural protein essential for epidermal barrier function. KPRP is a 699-amino acid, proline-rich (19%) insoluble protein expressed in the upper granular layer of stratified squamous epithelium, where it colocalizes with loricrin and associates with cytoskeletal structures 1. It functions as a marker of keratinocyte terminal differentiation, with expression initiating during late fetal skin development (E19 and later) 1. KPRP plays a critical mechanistic role in maintaining skin barrier integrity. KPRP deficiency impairs desmosome structure and reduces stratum corneum adhesion, leading to barrier dysfunction 2. Reduced KPRP expression is significantly associated with atopic dermatitis (AD) pathogenesis in both humans and animal models 2. The CREB-KPRP signaling axis regulates filaggrin and loricrin expression; PDE4 inhibition by difamilast increases KPRP levels via CREB phosphorylation, thereby restoring barrier proteins and providing therapeutic benefit in AD 3. Clinically, KPRP is induced by topical retinol treatment, contributing to improved epidermal architecture and reduced photoaging 4. KPRP expression reliably reflects in vivo terminal differentiation status in keratinocyte culture systems 5. Evolutionary analysis shows KPRP loss in cetaceans correlates with aquatic adaptation, highlighting its importance for terrestrial skin barrier function 6.