G3bp2, a member of the Ras-GAP SH3 domain binding proteins family, is an RNA-binding protein. It can bind with RNA or protein, regulating the nucleoplasmic shuttle. This protein is involved in multiple biological functions such as cell growth, differentiation, migration, and RNA and protein metabolism [1].

In tauopathies, G3bp2 directly interacts with Tau and inhibits Tau aggregation. Loss of G3bp2 in human neurons and brain organoids significantly elevates Tau pathology [2]. In non-small cell lung cancer, MG53, a TRIM protein family member, modulates G3bp2 activity. Knockdown of G3bp2 reduces the tumorigenicity of NSCLC cells [3]. In endothelial cells, G3bp2 is a critical oscillatory shear stress (OSS) regulated gene. G3bp2-/-Apoe-/-mice have decreased atherosclerotic lesions due to G3bp2 deficiency's impact on endothelial barrier function, monocyte adhesion, and pro-inflammatory cytokine levels [4]. In head and neck squamous carcinoma (HNSC), PRMT5-USP7-G3bp2 regulatory axis drives de novo lipogenesis and tumorigenesis [5]. In esophageal squamous cell carcinoma (ESCC), G3bp2, regulated by lncRNA LINC01554, facilitates metastasis by stabilizing HDGF transcript [6]. In pancreatic ductal adenocarcinoma (PDAC), knockdown of G3bp2 inhibits cell proliferation and invasion, and G3bp2 promotes gemcitabine resistance via regulating PDIA3-DKC1-hENT in a stress-granules-dependent manner [7]. In breast cancer, CAF-derived exosomal miR-92a downregulates G3bp2, enhancing cell migration and invasion [8].

In summary, G3bp2 is involved in a variety of biological processes and disease conditions. Studies using gene knockout or conditional knockout mouse models have revealed its role in neurodegenerative diseases like tauopathies, and in multiple cancers including lung, esophageal, pancreatic, and breast cancer, as well as in endothelial-related diseases such as atherosclerosis. These findings provide insights into potential therapeutic strategies targeting G3bp2 for these diseases.