KLK8

Kallikrein-related peptidase 8 (KLK8) is a secreted serine protease that modulates tissue remodeling and cellular signaling in multiple organs^[1][2]. KLK8 regulates cardiomyocyte hypertrophy through epidermal growth factor (EGF) signaling and protease-activated receptor (PAR) pathways, independent of kinin receptor activation^[1]. In vascular endothelium, KLK8 promotes endothelial-to-mesenchymal transition (EndMT) by cleaving VE-cadherin, facilitating plakoglobin nuclear translocation, and enhancing TGF-β1/Smad signaling, thereby contributing to diabetic cardiac fibrosis^[2]. Compared with other KLK family members, KLK8 exhibits tissue-specific expression in myocardium and brain and uniquely interacts with transcriptional regulators including p53 and HIF-1α^[2][3]. In neurodegenerative disease models, KLK8 inhibition ameliorates Alzheimer's disease pathology by modulating amyloid-beta precursor processing and tau hyperphosphorylation^[3]. KLK8 expression is responsive to muscarinic acetylcholine receptor (mAChR) agonists, linking its activity to dendritic growth and memory-related neuronal functions^[4]. Selective pharmacological modulation of KLK family members has been achieved using activity-based probes and peptide inhibitors, establishing proof-of-concept for therapeutic targeting of KLKs in cardiovascular, neurodegenerative, and dermatological contexts^[5][6]. These inhibitors demonstrate isoform-specificity, enabling distinction of KLK8 function from related KLKs in complex proteolytic cascades^[5][6].