SPRR2G (small proline-rich protein 2G) is a keratinocyte-specific protein that functions as a structural component of the cornified envelope. The protein localizes initially in the cell cytosol before becoming cross-linked to membrane proteins by transglutaminase, ultimately forming an insoluble envelope beneath the plasma membrane 1. This structural role is critical for barrier formation across epithelial surfaces. Beyond its canonical barrier function, SPRR2G expression is dynamically regulated in various pathological contexts. In HPV-positive head and neck squamous cell carcinomas, SPRR2G is highly expressed alongside other genes regulated by the NFX1-123/HR-HPV E6 axis 2. Similarly, SPRR2G is upregulated in vulvar squamous cell carcinomas 3 and shows altered expression patterns in breast cancer morphomolecular profiles 4. In inflammatory conditions, SPRR2G plays a pathological role in psoriasis. The lncRNA lnc-SPRR2G-2 drives keratinocyte hyperproliferation and inflammatory cytokine production (IL-1β, IL-8, CXCL10) through STAT3 pathway activation 5. Additionally, elevated SPRR2G expression correlates with conjunctival goblet cell loss and increased interferon-γ expression in aqueous tear deficiency 6. In wound healing contexts, SPRR2G expression facilitates keratinocyte differentiation during diabetic foot ulcer repair following tibial cortex transverse transport surgery 7. These findings suggest SPRR2G functions both as a structural barrier protein and as a regulated marker of keratinocyte differentiation in tissue remodeling and inflammatory disease.