Functional diversity of BAI1 (ADGRB1): From angiostasis to synaptic remodeling and disease therapeutics

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1), a member of the adhesion G protein-coupled receptor (ADGR) family, is regulated at the transcriptional level through epigenetic mechanisms (e.g., MBD2, EZH2, and p53) and alternative promoters, resulting in molecularly distinct isoforms via differential promoters usage (e.g., intron 17-derived variants) and post-translational processing (e.g., matrix metalloproteinase 14 [MMP-14]-mediated Vstat40 release). In cellular and animal studies, both the full-length BAI1 and its proteolytically released extracellular domains have been showed to exhibit multifaceted bioactivity, including inhibition of angiogenesis, suppression of tumor progression, and modulation of immune responses via interactions with CD36, integrins, lipopolysaccharide (LPS), and phosphatidylserine (PtdSer). Furthermore, BAI1 plays crucial roles in neurodevelopmental processes such as synaptic plasticity, neuronal differentiation, and cellular debris clearance, with emerging links to neuropsychiatric disorders. Despite significant advances, critical gaps remain in understanding isoform-specific functions and activation mechanisms across different tissues. This review systematically integrates current knowledge on BAI1, focusing on its genomic regulatory mechanisms, structural isoform diversity, and multidimensional biological functions. It also underscores the need to explore the translational potential of BAI1 in oncology, neurodegenerative diseases, and immune dysregulation, which is essential for advancing our understanding of this complex receptor and its therapeutic applications.