These results revealed that IHMT-337 as a novel agent that specifically and covalently bound to Cys663 residue within the EZH2-SET domain, leading to EZH2 protein misfolding or aggregation, then triggering EZH2 degradation through recruiting the Hsp70-interacting protein CHIP E3-mediated ubiquitination pathway in both DLBCL and TNBC. Here, STUB1 is linked to diffuse large B-cell lymphoma.