KLK5 (kallikrein-related peptidase 5) is a serine protease with dual roles in skin barrier homeostasis and pathological processes. Primary Function and Mechanism: KLK5 functions as a serine-type endopeptidase involved in epidermal desquamation through regulated proteolysis of cornified layer proteins 1. It operates within a tightly balanced proteolytic system with its cognate inhibitor LEKTI; LEKTI deficiency causes excessive KLK5 activity leading to uncontrolled desquamation 1. KLK5 also processes cathelicidin antimicrobial peptides and regulates innate immune responses in skin 2. Disease Relevance: KLK5 overexpression drives multiple pathologies. In inflammatory dermatoses, elevated KLK5 activity contributes to Netherton syndrome and atopic dermatitis, where dual inhibition of KLK5 and KLK7 restores barrier function 1. In rosacea, excessive KLK5-mediated LL-37 processing triggers inflammation 2. KLK5 serves as a host protease exploited by human betacoronaviruses, including SARS-CoV-2 and MERS-CoV, facilitating spike protein activation and viral replication 3. Clinical Significance: KLK5 expression is an independent predictor of poor prognosis in breast cancer (hazard ratios 2.37-3.03) 4, ovarian cancer 5, and cervical carcinoma, where KLK5/KLK7-dependent signaling promotes tumorigenesis through RhoA and NF-κB pathways 6. Conversely, KLK5 downregulation correlates with prostate cancer aggressiveness 7, suggesting context-dependent roles.