ZBTB49 (also known as ZNF509) is a zinc finger transcription factor that functions as a cell cycle regulator and potential tumor suppressor. The gene produces multiple isoforms through alternative splicing, with distinct functions in the DNA damage response 1. The long isoform (ZBTB49L) activates p21/CDKN1A transcription by binding its promoter and recruiting co-activator p300, while the short isoform (ZBTB49S1) activates RB transcription by antagonizing the MIZF repressor at the RB promoter 1. Both isoforms are induced by p53 upon genotoxic stress to inhibit cell proliferation 1. ZBTB49S1 additionally modulates p53 post-translational modifications by inhibiting p300-mediated K382 acetylation, thereby suppressing p53-driven PUMA transcription and preventing apoptosis under severe DNA damage 2. ZBTB49 shows tumor-suppressive characteristics, with high expression in normal epithelial cells but complete repression in colorectal, lung, and skin tumor tissues 1. In pathological contexts, ZBTB49 has been identified as a potential FOLFOX chemotherapy response predictor in colorectal cancer 3 and as a target of TGF-β-regulated miRNAs in lung fibroblasts 4, suggesting roles in therapy resistance and fibrotic disease pathogenesis.