Celastrol's Chemoproteomic Target in NK/T Lymphoma Is the NCOR2–HDAC3 Complex
- Celastrol cut viability of EBV-positive NK/T-cell lymphoma lines and slowed a short-term xenograft with more apoptosis markers.
- Chemical proteomics pulled down the corepressor NCOR2 near its deacetylase-activation domain; celastrol weakened NCOR2–HDAC3 association and inhibited recombinant HDAC3/NCOR2 activity.
- The result was shifted H3K27 acetylation, lipid-metabolic and stress transcriptional changes; an HDAC3 inhibitor partly reproduced them.
💡 Points Based on the abstract
Celastrol is a notoriously promiscuous electrophile, so a pull-down hit is where target validation starts, not ends. NCOR2 depletion partly changing the response helps, but an HDAC3 inhibitor only partially phenocopying says other targets are involved. I'd want a non-reactive analogue as a control, in vivo dosing beyond a short xenograft, and an exposure check, since celastrol's narrow therapeutic window is its long-standing problem.
📄 Paper · Biochemical Pharmacology ↗ Celastrol induces lipid-associated stress and apoptosis in EBV-positive extranodal NK/T-cell lymphoma with NCOR2–HDAC3 perturbation