Fig. 8. Illustration of how PARP-1 activity, facilitated by NEDD8-conjugated PARP-1, induces vascular calcification.

A diverse range of stimuli, such as inorganic phosphate (Pi) or VD₃, drive NEDD8 conjugation with PARP-1, which is mediated by CBL-b, and this process is reversed by NEDP-1. Notably, neddylation of PARP-1 leads to an increase in PARP-1 activity, which contributes to the progression of vascular calcification (VC). However, the NEDD8-activating E1 enzyme inhibitor MLN4924 effectively impedes the progression of VC. Additionally, a C373 peptide derived from CBL-b shows promise in preventing VC by mitigating the E3 ligase activity of the inactive form of CBL-b. Therefore, we propose that targeting the NEDD8-dependent activation of PARP-1 could be a potentially effective therapeutic approach for VC. Created with BioRender.com.