SERPINB5 (mammalian serine protease inhibitor) is a non-inhibitory serpin that functions as a context-dependent regulator of cancer progression. Unlike conventional serpins, SERPINB5 lacks serine protease inhibitory activity due to its inability to undergo the stress-to-relaxed conformational transition [UniProt]. In mammary tumors, SERPINB5 acts as a tumor suppressor, blocking growth, invasion, and metastatic properties [UniProt]. However, SERPINB5 exhibits paradoxical roles across different cancer types 1. In gastrointestinal cancers, SERPINB5 demonstrates context-dependent behavior—either promoting or suppressing tumorigenesis depending on subcellular localization and epigenetic modifications 1. In rectal and colorectal cancers, SERPINB5 promotes progression by interacting with HSP90AA1 to enhance proliferation and invasion 2, and by activating the TNF-α/NF-κB pathway to induce epithelial-mesenchymal transition and angiogenesis 3. Genetic variants of SERPINB5 influence cancer susceptibility: polymorphisms rs17071138 and rs8089104 increase oral cancer risk 4, while rs17071138, rs3744940, and rs3744941 variants associate with gallbladder cancer through altered gene expression regulation 5. Beyond malignancy, SERPINB5 regulates desmosomal adhesion through TGF-β signaling modulation, with therapeutic potential in pemphigus vulgaris treatment 6.