PAK1, also known as p21-Activated Kinase 1, is a serine/threonine-protein kinase. It is an effector protein of small G proteins Rac and Cdc42, regulating key cellular developmental processes such as cell motility, survival, proliferation, cytoskeleton and extracellular matrix organization, and transcription and translation [1,8]. It is involved in multiple oncogenic signaling pathways, making it a potential therapeutic target [1].

PAK1 has been implicated in various diseases. In melanoma, it may decrease cell sensitivity to programmed cell death, stimulate growth-promoting pathways, and contribute to an immunosuppressive tumor microenvironment, and its inhibition may enhance anti-melanoma therapies [2]. In glioblastoma, hypoxia-induced acetylation of PAK1 enhances autophagy and promotes tumorigenesis by phosphorylating ATG5, and silencing PAK1 can block autophagy and tumor growth [3]. In Down syndrome, suppressing the enhanced DSCAM/PAK1 pathway can reverse neurogenesis deficits in iPSC-derived cerebral organoids [4]. In cardiotoxicity, PAK1 is involved in cardiomyocyte programmed death, oxidative stress, and inflammatory responses [5]. In fibrosis, PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization, and loss of PAK1-dependent signaling can improve fibrosis [6]. A de novo PAK1 variant in the protein kinase domain has been associated with epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus [7]. In hepatocellular carcinoma, the USP14-CIB1-PAK1-ERK1/2 axis promotes lenvatinib resistance [9].

In conclusion, PAK1 is a crucial regulator of multiple cellular processes. Studies using genetic models (although not specifically KO/CKO mouse models in the provided references) have revealed its significant roles in cancer, neurological disorders, cardiotoxicity, and fibrosis. Understanding PAK1's functions and associated pathways provides potential therapeutic strategies for these diseases.