The UPR-oxidative stress nexus in diabetes and obesity: Exploring innovative therapeutic approaches for metabolic control

Abstract

Maintaining cellular protein homeostasis requires the endoplasmic reticulum (ER); however, the unfolded protein response (UPR) can be triggered by the accumulation of misfolded proteins, which can cause ER stress. The goal of the UPR is to bring the body back into balance. Nevertheless, long-term ER stress can cause β-cell dysfunction and apoptosis, which greatly exacerbates metabolic diseases such as diabetes and obesity. ER stress worsens insulin resistance and reduces glucose metabolism in pancreatic β-cells. Moreover, the ER is further damaged by oxidative stress, which is defined by an excess of reactive oxygen species (ROS), which prolongs metabolic dysfunction. This review delves into the molecular mechanisms that underlie ER stress, its consequences for diabetes and obesity, and possible treatment approaches. We discuss interventions to mitigate ER stress, including chemical chaperones, UPR modulators, and dietary strategies. Current pharmacological approaches, such as chemical chaperones and UPR modulators, have demonstrated efficacy in reducing ER stress, but they often present challenges, including inconsistent treatment responses and off-target effects. Antioxidant-rich dietary strategies, while promising for long-term management, require further validation to ensure their safety and effectiveness. Additionally, advances in CRISPR–Cas9 gene-editing technology provide new opportunities for addressing genetic defects associated with these disorders. These findings emphasize the need for integrated therapies that address both oxidative and ER stress to effectively mitigate metabolic dysfunction.