Klk5, also known as kallikrein-related peptidase 5, is a serine protease in the Kallikrein-related peptidases (KLK) family. It is involved in the regulation of epidermal desquamation, where its activity is balanced by the inhibitor lymphoepithelial Kazal type-related inhibitor (LEKTI) encoded by the serine peptidase inhibitor Kazal type 5 gene. Imbalances in this regulation can lead to skin-related pathologies [1].

In the context of Netherton syndrome (NS), a severe skin disease, Spink5⁻/⁻ mice (lacking LEKTI) show enhanced epidermal Klk5 protease activity and die shortly after birth due to skin barrier defects. However, when Klk5 is knocked out in Spink5⁻/⁻ mice (Spink5⁻/⁻Klk5⁻/⁻), neonatal lethality is rescued, the skin barrier defect is reversed, epidermal structure is restored, and skin inflammation is prevented. This indicates that Klk5 inactivation can reverse NS-like symptoms [3]. Additionally, in cervical cancer, Klk5 overexpression is associated with poor prognosis post-radiotherapy, increased radiation resistance in in vitro and in vivo models, suggesting its role in radioresistance [2].

In conclusion, Klk5 plays a crucial role in maintaining epidermal homeostasis, and its dysregulation is implicated in diseases like Netherton syndrome and cervical cancer. Gene-knockout mouse models, such as the Spink5⁻/⁻Klk5⁻/⁻ mice, have been instrumental in revealing Klk5's function in these disease conditions, providing potential therapeutic targets for treatment.