The authors reveal how TOP1 and MTA1 direct the epigenetic enzyme NSD2 to different genomic regions, placing H3K36me2 on gene bodies to support transcription and on repetitive sequences to activate th...

NSD2 coordinates the neurogenic-to-gliogenic transition in the developing neocortex through H3K36me2-dependent activation of EGFR–ERK signaling. Loss of NSD2 disrupts astroglial and oligodendroglial ...

Read the full paper: Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2

Nature, Published online: 30 June 2026; doi:10.1038/s41586-026-10816-w Retraction Note: NSD2 targeting reverses plasticity and drug resistance in prostate cancer

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Nature, Published online: 30 June 2026; doi:10.1038/s41586-026-10816-w Retraction Note: NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Nature, Published online: 30 June 2026; doi:10.1038/s41586-026-10816-wRetraction Note: NSD2 targeting reverses plasticity and drug resistance in prostate cancer

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Targeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. Relatively few E3s have been successfully utilized for TPD and the governing principles of functional ternary complex formation between the E3, degrader, and protein target remain elusive. FBXO22 has recently been harnessed for TPD applications by degraders that covalently modify its cysteine residues. Here, we reveal that the aldehyde derivative of UNC10088 promotes cooperative binding of FBXO22 to NSD2, a histone methyltransferase and oncogenic protein, leading to a cryo-EM structure of the SKP1-CUL1-F-box (SCF)-FBXO22 complex with NSD2. This structure revealed a conformational change in the FBXO22 loop surrounding C326, further exposing the cysteine for covalent recruitment. Additional medicinal chemistry efforts led to the discovery of benzaldehyde-based non-prodrug degraders that similarly engage C326