Ubiquitin proteasome system in cardiac fibrosis.

BACKGROUND

Cardiac fibrosis, including reactive fibrosis and replacement fibrosis, is a common pathological process in most cardiovascular diseases. The ubiquitin proteasome system (UPS) plays an important role in the development of fibrosis by mediating the degradation and synthesis of proteins involved in transforming growth factor-β (TGF-β)-dependent and TGF-β-independent fibrous pathways.

AIM OF REVIEW

This review aims to provide an overview of ubiquitinated and deubiquitinated molecules that participating in cardiac fibrosis, with the ultimate purpose to identify promising targets for therapeutic strategies.

KEY SCIENTIFIC CONCEPTS OF REVIEW

The UPS primarily impacts cardiac fibrosis through modulation of the TGF-β signaling pathway targeting key molecules involved, including the TGF-β receptors, Smad2/3/4 complexes, and inhibitory Smad7, thereby influencing fibrotic processes. In addition to its effect on TGF-β signaling, UPS also regulates pro-fibrotic pathways independent of TGF-β, including p53, AKT1-p38, and JNK1/2. Understanding these pathways is critical due to their involvement in diverse fibrotic mechanisms. The interplay between ubiquitination and deubiquitination of crucial pathways and molecules is pivotal in cardiac fibrosis and represents a promising area for identifying novel therapeutic targets. Different types of cardiac fibrosis involve distinct fibrotic pathways, leading to differential effects of ubiquitin ligases (E3 ligases) and deubiquitinating enzymes (DUBs) across various cardiac fibrotic diseases. Insights into UPS-mediated regulation of cardiac fibrosis provide potential anti-fibrotic therapeutic strategies, emphasizing the importance of targeting UPS components specific to the heart for effective therapy against cardiac fibrosis.