P21-activated kinase 4: a potent oncogene, molecular mechanisms and opportunities for targeted therapy.

[UNLABELLED] P21-activated kinase 4 (PAK4), recognized as a key effector protein of the Rho family of small G proteins Cell division regulatory protein 42 homologue (Cdc42) and Ras-related C3 botulinum toxin substrate 1 (Rac1), is a serine/threonine protein kinase that plays a critical role in a variety of biological processes.By analyzing the Tumour Immune Estimation Resource 2.0 (TIMER 2.0) databases, we observed that the expression level of PAK4 was significantly elevated in a wide range of tumors, and that its elevated expression level was strongly associated with poor patient prognosis. The activation of PAK4 plays an important role in promoting tumorigenesis and progression, which has been revealed by KEGG and GO analyses to play a key regulatory role in classical oncogenic signaling pathways, such as cell cycle, apoptosis, Ras signaling axis, PI3K/AKT, and P53, etc. Moreover, PAK4 plays an important function in tumor cell proliferation, migration invasion, cytoskeleton remodeling, and cell adhesion. In recent years, PAK4 has become a new target for therapeutic studies of antitumor drugs, and multiple types of PAK4 inhibitors have been gradually discovered. This review explores in detail the role of PAK4 in the following classical signaling pathways: PAK4/PI3K/AKT, PAK4/Wnt/β-catenin, PAK4/LIMK1/cofilin, and PAK4/MEK/ERK, and summarizes the PAK4-related inhibitors. The in-depth analysis of the classical pathway of carcinogenesis in this paper reveals the key role of PAK4 in cancer development and provides a theoretical basis for the development of novel PAK4 small molecule inhibitors.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12935-025-04042-z.