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

## TL;DR

This paper reviews how PAK4, a kinase, regulates metabolism and contributes to diseases like obesity and diabetes, suggesting it could be a target for new therapies.

## Contribution

The paper highlights novel regulatory mechanisms of PAK4 and its therapeutic potential in metabolic diseases.

## Key findings

- PAK4 overexpression is linked to metabolic disorders like obesity and diabetes.
- PAK4 inhibition improves metabolic parameters in experimental models.
- PAK4's activity is regulated by post-translational modifications and energy availability.

## Abstract

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.

This review article summarizes current evidence supporting PAK4 as an important regulator of metabolic homeostasis and disease. Researchers have found that PAK4 overexpression or sustained activation in adult tissues is closely linked to the progression of metabolic disorders, including obesity, metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. Studies using genetic and pharmacological approaches demonstrate that PAK4 modulates lipid and glucose metabolism through key signaling pathways involving HSL, FABP4, AMPK and NCoR1. Notably, PAK4 inhibition consistently improves metabolic parameters in experimental models, highlighting PAK4 as a promising therapeutic target for metabolic diseases. Future studies should focus on the development and optimization of selective PAK4 inhibitors to enhance therapeutic efficacy in these conditions.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.