The role of NRF2 function and regulation in atherosclerosis: an update

Abstract

Atherosclerosis, a chronic inflammatory disease of the arteries, remains a leading cause of cardiovascular morbidity and mortality worldwide. This review examines the molecular mechanisms underlying NRF2 role in atherosclerosis, focusing on the recently defined intricate interplay between autophagy, the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, microRNAs (miRNAs), and genes regulating NRF2 with atheroprotective effects. The NRF2/autophagy axis emerges as a critical regulator of cellular responses to oxidative stress and inflammation in atherosclerosis, with key players including Heat Shock Protein 90 (HSP90), Neuropeptide Y (NPY), and Glutaredoxin 2 (GLRX2). MiRNAs are identified as potent regulators of gene expression in atherosclerosis, impacting NRF2 signalling and disease susceptibility. Additionally, genes such as Prenyl diphosphate synthase subunit 2 (PDSS2), Sulfiredoxin1 (Srxn1), and Isocitrate dehydrogenase 1 (IDH1) are implicated in NRF2-dependent atheroprotective pathways. Future research directions include elucidating the complex interactions between these molecular pathways, evaluating novel therapeutic targets in preclinical and clinical settings, and addressing challenges related to drug delivery and patient heterogeneity. Despite limitations, this review underscores the potential for targeted interventions aimed at modulating NRF2/autophagy signalling and miRNA regulatory networks to mitigate atherosclerosis progression and improve cardiovascular outcomes.