G4 DNA potentiates KDM2B phase separation to couple transcriptional repression with immune remodeling in hepatocellular carcinoma.

Biomolecular condensates formed through liquid-liquid phase separation (LLPS) are emerging as key regulators of chromatin organization and gene expression. However, how phase separation is coupled to specific noncanonical DNA structures to confer locus-selective transcriptional regulation remains poorly understood. G-quadruplex DNA (G4 DNA) is enriched at promoters, CpG islands, and other regulatory genomic regions, suggesting a potential role in guiding chromatin regulators to defined genomic loci. KDM2B is a CpG island-binding chromatin regulator involved in transcriptional repression, yet whether and how it senses G4 DNA to establish gene-specific regulatory programs in hepatocellular carcinoma (HCC) remains unclear. Here, we identify KDM2B as a G4 DNA-responsive phase-separating chromatin regulator. KDM2B undergoes LLPS through its intrinsically disordered regions and preferentially recognizes parallel G4 DNA structures. Mechanistically, G4 DNA promotes KDM2B condensate assembly and facilitates its chromatin targeting to G4-and CpG-rich regulatory loci. This process establishes a local repressive chromatin environment and restrains inflammatory transcriptional programs. Conversely, loss of KDM2B impairs G4-dependent condensate formation and weakens chromatin-associated transcriptional repression, leading to a proinflammatory secretory phenotype characterized by increased cytokines and chemokines, including IL-6 and CXCL8. This inflammatory remodeling promotes SPP1+ macrophage accumulation, reshapes the tumor immune microenvironment, and accelerates HCC progression. Together, these findings reveal that KDM2B-G4 DNA phase-separated condensates function as an epigenetic regulatory platform that couples noncanonical genome architecture with locus-selective inflammatory gene repression, thereby restraining inflammation-associated HCC progression.