Klk8, also known as tissue kallikrein-related peptidase 8, is a tryptic serine protease with limited substrate specificity. It is involved in various biological processes. In the brain, it participates in activity-dependent synaptic changes like long-term potentiation. In the skin, it might be involved in desquamation through degrading epidermal adhesive molecules. It is also associated with multiple signaling pathways such as PI3K-Akt-mTOR, Notch, and EGF-dependent PI3K/Akt/mTOR in cancer-related contexts [2,3].

Genetic models, especially Klk8 knockout (KO) mouse models, have provided insights into its functions. In a CUMS-induced depression rodent model, Klk8 deficiency attenuated depression-like behaviors and hippocampal neuronal apoptosis, suggesting Klk8 upregulation promotes apoptosis via cleaving NCAM1 [1]. In TgCRND8 mice, genetic Klk8-knockdown led to a significant decline of amyloid beta (Aβ) and tau pathology in a sex-specific manner, improving structural neuroplasticity and memory performance, reinforcing its potential as a therapeutic target in Alzheimer's disease [4]. In diabetic mice, Klk8 deficiency alleviated diabetic cardiac fibrosis and rescued cardiac function, uncovering a pro-EndMT mechanism in diabetic cardiac fibrosis via Klk8 upregulation [5]. In hypoxia-induced H9c2 cardiomyocytes, Klk8 silencing attenuated cardiomyocyte hypertrophy, indicating its role in regulating right ventricular hypertrophy in hypoxic pulmonary hypertension [6].

In conclusion, Klk8 is a multifunctional protease involved in tissue development, synaptic changes, and disease-related processes. The study of Klk8 KO mouse models has significantly contributed to understanding its role in diseases such as depression, Alzheimer's disease, diabetic cardiomyopathy, and hypoxic pulmonary hypertension-related right ventricular hypertrophy, providing potential therapeutic targets for these conditions.