SPRED3 (Sprouty-related EVH1 domain containing 3) is a negative regulator of growth factor signaling that functions as a tyrosine kinase substrate inhibiting MAP kinase activation. The protein contains a cysteine-rich SPR domain that mediates interactions with regulatory enzymes, including zDHHC17-mediated S-acylation, a post-translational modification affecting its membrane localization and signaling capacity 1. SPRED3 inhibits FGF-induced signaling through suppression of ERK1/2 phosphorylation and blocks TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells. In pulmonary biology, miR-342-5p targets SPRED3 to protect against hyperoxia-induced bronchopulmonary dysplasia, where elevated Spred3 exacerbates lung injury and pulmonary arterial hypertension 2. Clinically, SPRED3 dysregulation associates with poor prognosis in multiple cancers. In thyroid carcinoma, elevated SPRED3 expression correlates with advanced tumor stage, increased metastatic risk, and poor overall survival, functioning as an independent prognostic factor 3. Mechanistically, SPRED3 promotes thyroid cancer cell proliferation through NF-κB signaling pathway activation 4. SPRED3 variants are also implicated in idiopathic hypogonadotropic hypogonadism as novel candidate genes 5, and altered SPRED3 expression in growth-restricted male fetuses may program reduced adipocyte differentiation capacity 6. SPRED3 methylation status serves as a prognostic biomarker in neuroblastoma 7.