NENF (neudesin neurotrophic factor) is a secreted neurotrophic factor that functions across multiple physiological systems. In the nervous system, NENF enhances neuronal survival in postnatal mature neurons and promotes proliferation and neurogenesis in embryonic neural progenitor cells 1. Its neurotrophic activity operates through MAPK1/ERK2, MAPK3/ERK1, and AKT1/AKT signaling pathways, with activity enhanced by heme binding 1. Beyond neurobiology, NENF regulates energy metabolism and adipocyte differentiation, promoting intramuscular and subcutaneous adipocyte development 2. Clinically, elevated NENF expression is associated with multiple malignancies. NENF acts as a causal risk gene for hepatocellular carcinoma (HCC) progression, promoting tumor-like stem cell properties and enhancing mRNA stemness scores 3. Circulating NENF demonstrates superior diagnostic performance to alpha-fetoprotein for HCC detection (AUC 0.67-0.99) and serves as an independent prognostic biomarker 4. In colorectal cancer, NENF co-localizes with PGRMC1 and enhances cancer cell invasiveness through progesterone signaling, with elevated serum NENF in patients 5. NENF depletion specifically inhibits cancer cell growth and invasiveness across liver, breast, and bladder cancers without affecting normal cells, while interfering with AKT, WNT, and MAPK pathways 6. Genetic variants in NENF are also associated with prostatitis risk 7.