Abstract

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is increasingly recognized as a state of chronic 
immunometabolic dysfunction driven in large part by oxidative stress and impaired antioxidant responses. 
Hyperglycaemia, dyslipidaemia, and adipose tissue inflammation collectively generate excessive reactive oxygen 
species (ROS), overwhelming endogenous antioxidant systems such as the Nrf2-Keap1 pathway, glutathione 
(GSH), thioredoxin, catalase, and superoxide dismutase. The resulting oxidative stress alters immune cell 
signalling, promotes inflammatory cytokine production, disrupts leukocyte recruitment, and impairs both innate 
and adaptive immune responses. This constellation of abnormalities-termed diabetic immunopathy-contributes to 
increased susceptibility to infections, impaired wound healing, suboptimal vaccine responses, and persistent 
low-grade inflammation that drives cardiometabolic complications. This review synthesizes mechanistic evidence 
on how antioxidant defense failure shapes immune dysregulation in diabetes, emphasizing the molecular pathways 
through which ROS modify immune receptors, disrupt cytokine signalling, promote post-translational 
modifications of proteins, and induce epigenetic reprogramming of immune cells. Additionally, it analyses the 
interplay between mitochondrial dysfunction, endoplasmic reticulum (ER) stress, ferroptosis, and immune cell 
exhaustion. Finally, emerging therapeutic strategies-including Nrf2 activators, mitochondrial-targeted 
antioxidants, dietary polyphenols, and metabolic modulators evaluated for their potential to restore redox balance 
and reverse immunopathy. Integrating immunology, redox biology, and metabolic disease, this article provides a 
comprehensive framework for understanding oxidative stress–driven immune dysfunction in diabetes and 
highlights potential precision interventions targeting redox–immune pathways.