SPRY4 (sprouty RTK signaling antagonist 4) is a negative regulator of receptor tyrosine kinase signaling. The protein suppresses insulin receptor and EGFR-transduced MAPK signaling by impairing GTP-Ras formation 1, and inhibits Ras-independent RAF1 activation 2. Additionally, SPRY4 represses integrin-mediated cell spreading through inhibition of TESK1-mediated cofilin phosphorylation 3. Clinically, SPRY4 mutations are associated with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome, where 14 individuals among 386 CHH patients carried mutations, implicating SPRY4 in the FGF signaling pathway critical for reproductive axis development 4. Notably, a heterozygous SPRY4 variant (p.Arg53Trp) was identified in infertile women, causing reduced oocyte potential and early embryonic arrest through disruption of oocyte redox homeostasis and mitochondrial function 5. In cancer biology, SPRY4 demonstrates context-dependent roles. In testicular germ cell tumors, elevated SPRY4 and its intronic transcript SPRY4-IT1 function as oncogenes, promoting cell growth via PI3K/Akt pathway activation 6. Conversely, the SPRY4-derived lncRNA SPRY4-IT1 consistently acts as an oncogenic biomarker across multiple cancer types, with high expression correlating with poor overall survival 78. Recent evidence demonstrates SPRY4 delivered via adipogenic BMSC exosomes impairs angiogenesis in steroid-induced osteonecrosis by suppressing the PTPRB/TIE2/PI3K axis 9.