ZFP91 is a zinc finger transcription factor and atypical E3 ubiquitin ligase with dual roles in gene regulation and protein degradation. As a transcription factor, ZFP91 binds conserved DNA motifs (CTTTAAR) with assistance from the Zincore coregulator complex to activate gene expression 1. As an E3 ligase, ZFP91 catalyzes lysine-63-linked ubiquitination of MAP3K14/NIK to stabilize and activate the non-canonical NF-κB2 pathway, and mediates lysine-48-linked ubiquitination of oncoproteins including E2F2, RIP1, and hnRNP A1 to promote their degradation. ZFP91 is markedly upregulated in acute myeloid leukemia, where it promotes cell proliferation and inhibits apoptosis by blocking RIP1 degradation 2. In pancreatic cancer, ZFP91 overexpression accelerates progression through β-catenin activation and drives chemoresistance 3. In gastric cancer, ZFP91 destabilizes FOXA1 to promote survival 4. Conversely, in hepatocellular carcinoma, ZFP91 functions as a tumor suppressor, inhibiting metabolic reprogramming by degrading hnRNP A1 and suppressing PKM2 splicing 5. In the tumor microenvironment, ZFP91 impairs tumor-infiltrating T cell metabolism and antitumor function by restricting mTORC1 activity 6. Clinically, next-generation cereblon E3 ligase degraders like CC-92480 selectively degrade ZFP91 and IKZF1 with enhanced potency compared to lenalidomide and pomalidomide in immunomodulatory-agent-resistant T-cell lymphomas 7. Molecular glue compounds including bufalin promote ZFP91-mediated E2F2 degradation as a strategy to overcome the undruggability of transcription factors 8.