PAK3, also known as p21-activated serine/threonine kinase 3, is a serine/threonine protein kinase. It is involved in multiple cellular processes such as cell migration, polarity regulation, and lipid metabolism. It is associated with pathways like mTOR and S6K1, and plays a crucial role in the development and function of the heart, brain, and in cancer progression [1,2,3]. Genetic models, especially KO/CKO mouse models, have been valuable in studying its functions.

In obesity cardiomyopathy, mice with cardiac-specific overexpression of PAK3 were more prone to cardiac dysfunction due to increased myocardial lipid deposition, as PAK3 promoted SREBP1c nuclear expression via mTOR/S6K1 activation [1]. In hepatocellular carcinoma, overexpression of PAK3 in cells promoted proliferation, migration, and invasion, and regulated EMT-related molecules and the TGF-β/smad pathway [2]. In the context of cranial irradiation, downregulation of PAK3 in mice led to cognitive impairment, and restoring PAK3 signaling via miR-206-3p antagonist could recover cognitive function [4]. Also, cardiac-specific PAK3 overexpression in mice caused pathological remodeling and deteriorated cardiac function, and PAK3 acted as an autophagy suppressor in cardiomyocytes [5].

In conclusion, PAK3 is essential in regulating lipid homeostasis in the heart, metastasis in hepatocellular carcinoma, cognitive function after cranial irradiation, and autophagy in the heart. The study of PAK3 using KO/CKO mouse models has provided valuable insights into its role in these disease-related biological processes, which may contribute to the development of new therapeutic strategies.