GFRA1 (GDNF family receptor alpha 1) functions as a GPI-linked coreceptor for glial cell-derived neurotrophic factor (GDNF), playing critical roles in neuronal development and survival 1. The protein facilitates GDNF binding, which leads to autophosphorylation and activation of the RET receptor tyrosine kinase, promoting neuronal survival through PI3K/AKT and ERK1/2 signaling pathways 1. In the reproductive system, GFRA1 is essential for spermatogonial stem cell regulation, with high expression marking stem cells that decrease as cells differentiate 2. GFRA1 also modulates human spermatogonial stem cell proliferation and survival through interactions with pleiotrophin signaling 3. Beyond its physiological roles, GFRA1 contributes to disease pathogenesis. In osteosarcoma, cisplatin treatment induces GFRA1 expression, which promotes chemoresistance by activating SRC-AMPK-dependent autophagy pathways, independent of RET signaling 45. Additionally, GFRA1 facilitates breast cancer metastasis through epigenetic regulation involving extracellular vesicle-mediated lncRNA SOX9-AS1 6. While GFRA1 was initially investigated as a candidate gene for Hirschsprung disease due to its role in RET signaling, genetic studies found no significant association 7. These findings highlight GFRA1's dual role in normal development and cancer progression.