Venetoclax attenuates vascular calcification through combined senolytic activity and SOX9/LH3-mediated ECM remodeling

Background Despite classical risk factors revised, cardiovascular mortality remains high level because of the high residual risk like vascular calcification (VC). There is now a consensus that vascular calcification is a key independent driver of adverse cardiovascular events. Yet, no effective therapeutic interventions currently exist. Senescence driving the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) is the core mechanism. Senescent cells are characterized by a unique balance of apoptotic stress and anti-apoptotic defenses. Senolytics are a class of drugs designed to rebuild apoptotic pathways to selectively eliminate these cells. Venetoclax, a next-generation highly selective BCL-2 inhibitor, offers superior specificity and safety profiles and has become a first-line therapy for many blood cancers. However, clinical evidence regarding its senolytic efficacy in non-oncologic settings is virtually nonexistent. Aims We aimed to demonstrated the protection of Venetoclax for VC both in bench and clinical cohort. Methods and Results Using GSE database, Western blot, immunofluorescences and immunohistochemical, experiments were conducted both in vivo and in vitro. Here, we demonstrate that BCL2 acts as the key anti-apoptotic protein upregulated in senescence-related VC, by which promotes VC through extracellular matrix (ECM) remodeling. Treatment with VNT alleviates VC and reduces vascular senescence in vitro and in vivo. Mechanistically, VNT activates senescence-specific apoptosis and promotes the degradation of sex determining region Y box protein 9 (SOX9). Consequently, it alleviates VC by downregulating the SOX9/lysine hydroxylase 3 (LH3)/ECM remodeling pathway. Moreover, administration of VNT significantly correlates with risk reduction of severe VC in clinical cohort. Conclusion Collectively, our findings underscore the BCL2 positive VSMCs is a central driver of ECM remodeling following VC. With clinical trial safety, VNT present promising approaches for VC therapy translation.