Pharmacological Destabilization of ZEB2 Attenuates Atherosclerosis via Restoration of Lipid Catabolism

We further developed TB15, a novel small molecule that selectively destabilizes ZEB2 protein by promoting deacetylation-dependent ubiquitination and proteasomal degradation without affecting ZEB2 transcription. To enable precision therapy, an RGD-functionalized mesoporous polydopamine nanoparticle delivery system was engineered to target phenotypically transformed VSMCs within atherosclerotic plaques, achieving superior therapeutic efficacy with minimal systemic toxicity.

Notably, machine learning–based drug response modeling (BFReg-NN) predicted optimal anti-atherosclerotic efficacy when TB15 was combined with fluvastatin or pitavastatin, nominating a rational combination strategy. Together, this work defines the ZEB2-Mc2r axis in atherosclerosis, presents a first_x001E_in_x001E_class ZEB2 degrader, and demonstrates a targeted nanotherapeutic approach with strong translational potential for precision treatment of atherosclerotic disease.