DTX2 is an E3 ubiquitin ligase containing WWE and RING-finger domains that functions as a multifaceted regulator in cell signaling and disease processes 1. As a Notch pathway regulator, DTX2 mediates both positive and negative signaling depending on cellular context, though recent literature emphasizes its emerging roles in cancer biology 1. Mechanistically, DTX2 catalyzes K48-linked ubiquitination of diverse substrates including FTO (m6A demethylase), NCOA4 (ferritinophagy regulator), HSD17B4 (peroxisomal β-oxidation enzyme), and histone H2B, targeting them for proteasomal degradation 2345. Additionally, DTX2 is recruited to DNA double-strand breaks via ADP-ribosylation-dependent mechanisms through its WWE and DELTEX domains, regulating homologous recombination pathway choice 6. DTX2 also ubiquitylates ADP-ribosylated DNA and RNA, representing a non-proteinaceous substrate function 7. Clinically, DTX2 is upregulated across multiple cancers (NSCLC, HCC, glioma, melanoma) and promotes tumorigenesis by suppressing ferroptosis, facilitating immunotherapy resistance, and enhancing tumor-associated neutrophil infiltration 3458. DTX2 inhibition sensitizes tumors to immunotherapy, ferroptosis inducers, and genotoxic agents, positioning it as a promising therapeutic target.