SPRR1B encodes a small proline-rich protein that functions as a cross-linked envelope precursor in keratinocytes. The protein is induced during squamous differentiation and becomes covalently incorporated into the cornified envelope through transglutaminase-mediated cross-linking, serving both as an amine donor and acceptor in this process 1. SPRR1B expression is regulated by differentiation signals and can be induced by UV irradiation and phorbol esters while being repressed by retinoids 23. Beyond its canonical role in skin barrier formation, SPRR1B has emerged as a biomarker in multiple disease contexts. In psoriasis, SPRR1B is significantly upregulated and correlates with macrophage and T cell infiltration; knockdown studies show it regulates inflammatory cytokines IL-17 and IL-22 4. In oral squamous cell carcinoma, SPRR1B promotes proliferation via mitogen-activated protein kinase p38 phosphorylation and correlates with differentiation status 5. In lung adenocarcinoma, high SPRR1B expression associates with worse prognosis, and silencing reduces proliferation while activating the MAPK signaling pathway 6. Recent evidence suggests SPRR1B+ keratinocytes activated via STAT3 signaling facilitate accelerated wound healing in oral mucosa 7. A pan-cancer stemness signature identified SPRR1B among genes whose knockout enhanced tumor immune response, proposing it as a potential immunotherapy target 8.