DNA polymerase beta (POLB) is a repair polymerase essential for base-excision repair (BER), a critical DNA damage response pathway. POLB functions by removing 5'-deoxyribose-phosphate from abasic sites through its 5'-dRP lyase activity and catalyzes single-nucleotide gap-filling through its polymerase activity in a distributive rather than processive manner 12. Beyond nuclear BER, POLB localizes to mitochondria and maintains mitochondrial DNA integrity through mitochondrial BER 3. Clinically, POLB mutations are highly prevalent in human tumors. Colorectal cancers harbor POLB coding mutations in 40% of cases, with many variants reducing enzyme activity and compromising BER function, thereby promoting genomic instability 4. Promoter polymorphisms in POLB affect transcriptional regulation, with some mutations associated with thymic hyperplasia in Chinese populations 5. A gastric cancer-associated T889C POLB mutation correlates with increased progesterone receptor expression and intraperitoneal metastasis 6. Therapeutically, POLB emerges as a synthetic lethal partner with PARP inhibitors (PARPis) specifically in BRCA-mutated cancers 7. POLB knockout combined with PARPi treatment enhanced tumor regression in xenograft models, suggesting POLB as a promising target for improving PARPi efficacy in homologous recombination-deficient malignancies. BER/SSBR proteins including POLB also mediate resistance to PARG inhibitors through replication-associated mechanisms 8.