ASF1B is a histone chaperone that facilitates histone H3-H4 deposition during replication-dependent chr19 assembly, working cooperatively with CAF-1 and importin-4 to recognize newly synthesized histones bearing specific post-translational modifications. The protein does not participate in replication-independent nucleosome assembly, distinguishing it functionally from its paralog ASF1A. ASF1B is significantly overexpressed across multiple cancer types and associates with poor prognosis in hepatocellular carcinoma and pancreatic adenocarcinoma. In acute myeloid leukemia (AML), IL-1β-mediated upregulation of ASF1B promotes leukemic progression through the TLK-ASF1 pathway, which regulates cell cycle and DNA damage responses 1. ASF1B depletion reduces leukemic cell growth in both in vitro and in vivo models while remaining dispensable for normal hematopoiesis. In gastric cancer, ASF1B promotes tumor progression by downregulating H2AC20 and activating PI3K/AKT and ERK1/2 signaling pathways 2; this process is also regulated by the FOXM1 transcription factor, and targeting FOXM1 with thiostrepton suppresses ASF1B-driven cancer progression 3. In cervical cancer, ASF1B stabilizes CDK9 to drive proliferation 4. In pancreatic cancer, ASF1B increases H3K56 acetylation to promote c-Myc expression, and inhibitors of CBP and c-Myc reverse this effect 5. The TLK-ASF1 pathway and FOXM1-ASF1B axis represent promising therapeutic targets across diverse cancer subtypes.