Klk8, also known as tissue kallikrein-related peptidase 8, is a trypsin-like serine protease. It has limited substrate specificity and is involved in various biological processes. In the brain, it is implicated in activity-dependent synaptic changes such as long-term potentiation [2]. It may also be involved in tissue development and rearrangement, for example, in the desquamation process in the skin epidermis through degrading adhesive molecules [2].

In a CUMS-induced depression rodent model, transgenic overexpression of Klk8 exacerbated, while Klk8 deficiency attenuated depression-like behaviors and hippocampal neuronal apoptosis. Klk8 was found to proteolytically cleave the NCAM1 extracellular domain, and both overexpression of NCAM1 and its mimetic peptide rescued Klk8-overexpressed neuron cells from apoptosis, suggesting Klk8 contributes to depression-related apoptosis via NCAM1 cleavage [1]. In TgCRND8 mice, genetic Klk8-knockdown led to a significant decline of amyloid beta (Aβ) and tau pathology, and an improvement of structural neuroplasticity in a sex-specific manner, reinforcing its potential as a therapeutic target in Alzheimer's disease [3]. In addition, Klk8 deficiency attenuated diabetic cardiac fibrosis and rescued impaired cardiac function in diabetic mice, and siRNA-mediated Klk8 knockdown in human coronary artery endothelial cells alleviated high-glucose-induced endothelial damage and EndMT, uncovering a pro-EndMT mechanism in diabetic cardiac fibrosis [4].

In conclusion, Klk8 is a multifunctional protease involved in synaptic changes, tissue development, and has a significant impact on diseases such as depression, Alzheimer's disease, and diabetic cardiomyopathy. Gene knockout mouse models have been crucial in revealing its role in these disease conditions, highlighting its potential as a therapeutic target for these diseases.