SPRY3 (sprouty RTK signaling antagonist 3) is a pseudoautosomal region 2 (PAR2) gene that functions as a negative regulator of growth factor signaling pathways. SPRY3 inhibits receptor tyrosine kinase (RTK) signaling by suppressing the MAPK/ERK cascade 1, fibroblast growth factor (FGF) receptor signaling, and epidermal growth factor (EGF)-mediated p42/44 ERK activation. In the nervous system, SPRY3 negatively regulates neurite branching and arborization; transient overexpression inhibits neurite growth while knockdown promotes it 2. SPRY3 has emerging clinical significance in multiple disease contexts. In myocardial infarction, miR-143-3p-mediated suppression of SPRY3 promotes cardiac fibrosis through P38, ERK, and JNK pathway activation 1. In acute myeloid leukemia, loss of SPRY3 expression confers resistance to FLT3 inhibitor AC220 by reactivating FGF/Ras/ERK signaling 3. Y-chrX|Y-derived linc-SPRY3 transcripts enhance radiation sensitivity in male non-small cell lung cancer and correlate with improved overall survival 4. Additionally, SPRY3 maps adjacent to autism susceptibility gene TMLHE, and altered SPRY3 expression patterns in cerebellar Purkinje cells may contribute to autism pathology, particularly explaining the male bias in autism prevalence 25. SPRY3 silencing is maintained through multiple epigenetic mechanisms including histone modifications, Polycomb recruitment, and late replication timing, independent of DNA methylation 6.