PYCR2 (pyrroline-5-carboxylate reductase 2) is an oxidoreductase that catalyzes the final step of proline biosynthesis by reducing pyrroline-5-carboxylate to L-proline using NAD(P)H, with higher specific activity in the presence of NADH 1. Beyond proline synthesis, PYCR2 participates in cellular responses to oxidative stress 2 and collaborates with RRM2B to protect cells from oxidative damage 3. In some cell types like erythrocytes, it may primarily generate NADP+ 4. PYCR2 plays significant roles in cancer metabolism and progression. It is overexpressed in hepatocellular carcinoma, colorectal cancer, and breast cancer, where it promotes tumorigenesis through multiple mechanisms. In HCC, PYCR2 activates the AKT signaling pathway to enhance glycolysis and cell viability 5. In colorectal cancer, it promotes progression via PI3K/AKT/mTOR pathway activation 6 and Wnt/β-catenin signaling through MASTL regulation 7. In breast cancer, c-Myc transcriptionally upregulates PYCR2 to promote invasion and metastasis via AKT activation 8. Clinically, PYCR2 deficiency causes hypomyelinating leukodystrophy 10 9, though proline auxotrophy may not be the primary disease mechanism. Recent evidence suggests proline supplementation can restore mitochondrial function and reverse aging hallmarks in senescent cells 10, indicating therapeutic potential beyond cancer contexts.