SEMA5A (semaphorin 5A) is a bifunctional axonal guidance cue that regulates neuronal development and immune responses through distinct proteoglycan interactions 1. The protein exerts attractive effects via heparan sulfate proteoglycan binding and inhibitory effects through chondroitin sulfate proteoglycan interactions, with seven thrombospondin type-1 repeats (TSR1-7) mediating these interactions 1. SEMA5A acts as a ligand for plexin receptors (PLXNB3, PlexinA1), triggering cytoskeletal rearrangement and inhibiting cell migration in glioma cells [UniProt function]. In the immune system, SEMA5A-PlexinA1 signaling promotes Th17 cell differentiation via PI3K/Akt/mTOR pathway activation, contributing to autoimmune disease progression 2. SEMA5A also facilitates angiogenesis by promoting endothelial cell proliferation and migration 3. Clinically, SEMA5A variants associate with hippocampal volume and cognitive performance 4, while elevated SEMA5A contributes to rheumatoid arthritis and systemic lupus erythematosus pathogenesis 52. Notably, SEMA5A deletion alters synaptic connectivity and social behavior in mice, linking it to autism 6. The rs7702187 SNP associates with Parkinson's disease risk in Western populations 7, and SEMA5A downregulation in cancer cells promotes tumor progression 8. These findings establish SEMA5A as a multifunctional molecule with therapeutic potential across neurological and autoimmune disorders.