PLEKHG4B is a guanine nucleotide exchange factor (GEF) that specifically activates the small GTPase CDC42 by catalyzing GDP-to-GTP exchange. This function enables its primary role in regulating actin cytoskeletal remodeling during late-stage cell-cell junction formation by controlling actin filament contractility, facilitating the transition from 'open' to 'closed' junctions. Beyond junction formation, PLEKHG4B exhibits disease-relevant roles in multiple malignancies. In hepatocellular carcinoma (HCC), PLEKHG4B is frequently targeted by HBV integration and functions downstream of the circ_0008043/miR-661 axis to promote cell migration and epithelial-mesenchymal transition 1 2. A super-enhancer-associated PLEKHG4B variant contributes to bladder cancer prognosis prediction 3, while elevated PLEKHG4B expression associates with ovarian cancer recurrence risk 4. Clinically, a missense variant (rs150706952, A432V) in PLEKHG4B shows significant association with white matter and gray matter diffusivity in type 2 diabetes populations, suggesting neurological involvement 5. Additionally, PLEKHG4B expression is differentially regulated in uterine fibroids in a race/ethnicity-dependent manner 6. These findings indicate PLEKHG4B functions beyond cytoskeletal regulation in disease pathogenesis, positioning it as a potential therapeutic target across multiple cancer types and metabolic conditions.