PYCR1 (pyrroline-5-carboxylate reductase 1) is a mitochondrial oxidoreductase that catalyzes the final step in proline biosynthesis by reducing pyrroline-5-carboxylate to L-proline using NAD(P)H as cofactor 1234. The enzyme shows higher specific activity with NADH at physiologic concentrations 13. Beyond its metabolic role, PYCR1 functions in cellular stress responses and has gained prominence in cancer biology. In cancer-associated fibroblasts (CAFs), PYCR1-mediated proline synthesis supports collagen production and pro-tumorigenic extracellular matrix deposition 5. The enzyme promotes tumor progression through multiple mechanisms, including regulation of glycolysis and enhancement of cell proliferation and metastasis in hepatocellular carcinoma via IRS1 expression modulation through histone lactylation 6. PYCR1 also exhibits non-enzymatic nuclear functions, where IGF1R-mediated phosphorylation enables its interaction with transcription factor ELK4 to regulate gene expression under hypoxic conditions 7. Additionally, PYCR1 contributes to mitochondrial homeostasis and cellular senescence reversal, with proline supplementation activating mitophagy pathways and restoring mitochondrial function in aging cells 8. Mutations in PYCR1 are associated with autosomal recessive cutis laxa disorders, highlighting its clinical significance in connective tissue biology.