NDRG3 (NDRG family member 3) is a multifunctional protein that serves as a key mediator of cellular responses to metabolic stress, particularly hypoxia and lactate signaling. The protein adopts an α/β-hydrolase fold but lacks catalytic activity due to substitution of canonical catalytic triad residues 1. Under normoxic conditions, NDRG3 is degraded through a PHD2/VHL-dependent pathway, but hypoxia-induced lactate accumulation protects NDRG3 from degradation by direct lactate binding 2. Stabilized NDRG3 activates the Raf-ERK pathway by binding c-Raf, promoting angiogenesis and cell growth 2. The protein plays critical roles in neuronal differentiation, where lactate treatment enhances NDRG3 expression and promotes neurite extension through both NDRG3-dependent and independent mechanisms involving transcription factors TEAD1 and ELF4 3. NDRG3 also functions as a scaffolding protein that facilitates KRAS deubiquitination by promoting interaction between KRAS and USP9X deubiquitinase, thereby maintaining KRAS protein levels in KRAS-driven cancers 4. Clinically, NDRG3 shows tissue-specific expression patterns, being highly expressed in testis, prostate, and ovary 5, and serves as a tumor promoter in prostate cancer while functioning as a protective factor in thyroid cancer 67.