Recent Advances in KEAP1/NRF2-Targeting Strategies by Phytochemical Antioxidants, Nanoparticles, and Biocompatible Scaffolds for the Treatment of Diabetic Cardiovascular Complications

Abstract
Significance: Modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response is
a key aspect in the onset of diabetes-related cardiovascular complications. With this review, we provide an
overview of the recent advances made in the development of Nrf2-targeting strategies for the treatment of
diabetes, with particular attention toward the activation of Nrf2 by natural antioxidant compounds, nanoparticles,
and oxidative stress-modulating biocompatible scaffolds.
Recent Advances: In the past 30 years, studies addressing the use of antioxidant therapies to treat diabetes have
grown exponentially, showing promising but yet inconclusive results. Animal studies and clinical trials on the
Nrf2 pathway have shown promising results, suggesting that its activation can delay or reverse some of the
cardiovascular impairments in diabetes.
Critical Issues: Hyperglycemia- and oscillating glucose levels-induced reactive oxygen species (ROS) accumulation
is progressively emerging as a central factor in the onset and progression of diabetes-related cardiovascular
complications, including endothelial dysfunction, retinopathy, heart failure, stroke, critical limb
ischemia, ulcers, and delayed wound healing. In this context, accumulating evidence suggests a central role for
Nrf2-mediated antioxidant response, one of the most studied cellular defensive mechanisms against ROS
accumulation.
Future Directions: Innovative approaches such as tissue engineering and nanotechnology are converging
toward targeting oxidative stress in diabetes. Antioxid. Redox Signal. 36, 707–728