PLEKHA4 (pleckstrin homology domain containing A4) functions as a critical regulator of Wnt signaling pathways through its interaction with membrane phospholipids and E3 ubiquitin ligase complexes. The protein oligomerizes into clusters at PI(4,5)P2-rich plasma membrane regions where it recruits the Cullin-3 (CUL3) E3 ubiquitin ligase substrate adaptor KLHL12, thereby decreasing CUL3-KLHL12-mediated polyubiquitination of Dishevelled, a central intermediate in both canonical and non-canonical Wnt signaling 1. This mechanism allows PLEKHA4 to positively regulate Wnt/β-catenin signaling and planar cell polarity pathways 1. PLEKHA4 is significantly overexpressed in multiple cancer types, including melanoma, glioblastoma, and lower-grade glioma, where high expression correlates with poor prognosis and aggressive tumor behavior 234. In cancer cells, PLEKHA4 promotes proliferation by facilitating G1-S cell cycle transition, inhibiting apoptosis, and enhancing cell migration through modulation of MAPK signaling pathways and β-catenin nuclear translocation 25. Additionally, PLEKHA4 influences tumor microenvironment remodeling by promoting M2 macrophage infiltration and polarization 36. The protein has emerged as a promising therapeutic target, with knockdown studies demonstrating significant tumor growth inhibition in various cancer models 235.