SPRY3 is a negative regulator of receptor tyrosine kinase (RTK) signaling pathways, particularly FGF and EGF signaling cascades. It inhibits the MAPK/ERK pathway and suppresses extracellular matrix protein accumulation, and in the nervous system, it constrains neurite branching and complexity. SPRY3 maps to the pseudoautosomal region 2 (PAR2) on the X and Y chrX|Y; the Y-linked allele is epigenetically silenced through histone modifications and delayed replication rather than DNA methylation. SPRY3 is highly expressed in neural tissues, including cerebellar Purkinje cells and retinal ganglion cells, where it regulates neuronal morphology. Loss of SPRY3 expression drives resistance to FLT3 inhibitors in acute myeloid leukemia (AML) by reactivating FGF/Ras/ERK signaling 1. In cardiac fibrosis after myocardial infarction, miR-143-3p-mediated suppression of SPRY3 promotes fibroblast activation and excessive extracellular matrix deposition through P38, ERK, and JNK pathway activation 2. SPRY3 has been proposed as a candidate autism susceptibility locus given its proximity to TMLHE, its expression pattern in cerebellar regions exhibiting Purkinje cell loss in autism, and differential regulation between males and females 3. In male non-small cell lung cancer, Y chrX|Y-derived long noncoding RNA transcribed from the SPRY3 locus (linc-SPRY3-2/3/4) enhances radiation sensitivity and overall survival by destabilizing oncogenic transcripts via IGF2BP3 interaction 4. The role of SPRY3 in glioblastoma and neuroblastoma remains incompletely characterized 5.