Kallikrein-Related Peptidase 5 Is Associated with Tumor Progression, KRT19 Expression, and Distinct Molecular Programs in High-Grade Serous Ovarian Cancer

Background/Objectives: High-grade serous ovarian cancer (HGSOC) is characterized by peritoneal dissemination and ascites formation. Kallikrein-related peptidase 5 (KLK5) has been linked to aggressive disease. Building on evidence linking KLK4–7 to keratin 19 (KRT19), we hypothesized that a KLK5–KRT19 axis contributes to tumor progression and investigated this potential axis alongside broader KLK5-associated tumor-cell, metabolic, signaling, and microenvironmental mechanisms. Methods: KLK5-overexpressing ovarian cancer models were characterized using functional assays (adhesion, migration, spheroid formation), KRT19 expression analysis, proteomics, and gene set enrichment analysis. The putative KRT19–KLK5 axis was further investigated in vivo, in silico, and by immunohistochemistry. KLK5-dependent tumor progression was assessed in vivo, including survival and ascites formation, with quantification of CXCL9 in ascitic fluid. Clinical relevance was evaluated by immunohistochemistry in an HGSOC cohort. Results: In vitro, KLK5 overexpression induced KRT19 expression and enhanced spheroid formation, whereas effects on adhesion and migration were limited. Proteomic analysis identified KLK5-associated alterations in cholesterol homeostasis, coagulation, and mTORC1 signaling. In the in vivo mouse model, KLK5 overexpression was associated with reduced survival and increased ascites formation, and KLK5 induced intratumoral KRT19 expression. KLK5 and KRT19 protein levels were positively associated in patient tumors and primary ascites-derived tumor cells. In ascites, KLK5 overexpression was associated with reduced CD3+ cell abundance and lower CXCL9 concentrations. Conclusions: KLK5 promotes HGSOC progression. Its association with KRT19 expression, altered cholesterol homeostasis and mTORC1 signaling, reduced CD3+ cells and CXCL9 in ascites suggests that KLK5 contributes to both tumor-cell and immune features of HGSOC.