PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications

Here we highlight recent advances in understanding the regulatory role of p21-activated kinase 4 (PAK4), the prototypical group II PAK family member, in metabolic diseases. It also briefly notes the contributions of the group I member PAK1 in metabolic tissues. Activation of PAK4 is mediated by upstream Ras-related small GTPases such as Cdc42 and Rac1. In addition to this classical mechanism, post-translational modifications triggered by growth factors and hormonal signals are now recognized as key determinants of PAK4 activity and expression. Notably, phosphorylation-dependent ubiquitination followed by proteasomal degradation-initiated by changes in cellular energy availability-has emerged as an important mechanism regulating PAK4 protein stability. PAK4, in turn, phosphorylates a broad range of intracellular signaling proteins and transcriptional regulators, thereby orchestrating communication among the liver, adipose tissue and skeletal muscle. Accumulating evidence indicates that aberrant overexpression of PAK4 contributes to the progression of metabolic diseases, whereas reduced PAK4 activity may provide protective benefits. These insights collectively support the therapeutic potential of targeting PAK4 in obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Moreover, recognition of PAK4's kinase-independent scaffold functions has stimulated the development of PAK4-targeted protein degraders, expanding therapeutic opportunities.