PENK (proenkephalin) is a neuropeptide precursor gene located on chromosome 8 that encodes opioid peptides involved in pain and stress regulation. As a member of the opioid/orphanin gene family alongside POMC, PDYN, and PNOC 1, PENK functions through G protein-coupled opioid receptor signaling pathways and is expressed in diverse neural tissues including the hypothalamic paraventricular nucleus, where it modulates neuroendocrine and autonomic functions 2. PENK expression is sexually dimorphic in neuropathic pain states, with elevated PENK levels detected in female dorsal root ganglia associated with neuropathic pain, suggesting sex-specific mechanisms in pain processing 3. Clinically, PENK methylation serves as a noninvasive biomarker for early bladder cancer detection, demonstrating 86.5% sensitivity and 92.5% specificity for high-grade and advanced tumors 4, with superior performance compared to conventional urinary tests 5. Additionally, plasma proenkephalin concentrations show diagnostic efficacy above 0.70 for predicting persistent acute kidney injury, though with limited validation studies 6. Reduced PENK expression characterizes invasive non-functional pituitary neuroendocrine tumors, suggesting a tumor-suppressive role 7. These findings position PENK as both a physiological regulator of pain and neuroendocrine function and a promising molecular biomarker for cancer and kidney disease.