Endometriosis, a prevalent gynecological condition, is characterized by the growth of endometrial-like tissues outside the uterus, leading to severe pain and infertility in affected women. The pathogenesis of endometriosis remains elusive, and effective treatments are limited, highlighting the need for a deeper understanding of its molecular mechanisms. A pivotal role of P21-activated kinase 5 (PAK5) in endometriosis progression has been uncovered, revealing that PAK5-mediated phosphorylation of pyruvate kinase M2 (PKM2) is critical for anaerobic glycolysis in endometriotic cells. This discovery provides novel insights into the disease's pathophysiology and suggests potential therapeutic targets.

The study delved into the role of PAK5 in endometriosis, investigating its impact on cellular functions such as proliferation, migration, and invasion. PAK5 was found to enhance these capabilities in endometrial epithelial cells, suggesting its role in disease progression. The research further explored the interaction between PAK5 and PKM2, an enzyme integral to glycolytic activity. PKM2's elevated levels in cancer cells are well-documented, but its post-translational modification in endometriosis has been less examined. This study fills the gap by demonstrating that PAK5 promotes PKM2 protein stability through phosphorylation at the Ser519 site, indicating a potential mechanism for PAK5's action in endometriosis.

Experiments conducted included cell culture manipulations, tissue collection, and immunohistochemical analyses to assess the expression and activity of PAK5 and PKM2. The results showed that PAK5 overexpression increased PKM2 protein levels and activity, leading to enhanced glycolysis and endometriotic cell growth. Conversely, PAK5 knockdown reduced PKM2 levels and cellular capabilities, implicating PAK5 as a positive regulator of endometriosis. The study also utilized a small-molecule PAK inhibitor, GNE 2861, to inhibit endometriosis cell proliferation and migration, further supporting the significance of the PAK5-PKM2 axis in endometriosis.

The findings from this research underscore the importance of PAK5 in endometriosis, highlighting its potential as a therapeutic target. By targeting PAK5, it may be possible to modulate PKM2 activity and subsequently affect anaerobic glycolysis, a critical process in endometriosis. This study's contributions to the field are significant, as they not only advance the understanding of endometriosis pathophysiology but also pave the way for developing targeted therapies that could improve the treatment landscape for women suffering from this debilitating condition.
DOI: 10.1007/s11684-024-1069-3