Oxidative stress in diabetic peripheral neuropathies: Key mechanisms and therapeutic targets

Oxidative stress plays a central and multifaceted role in the pathogenesis of diabetic peripheral neuropathies (DPN), one of the most common and disabling complications of diabetes mellitus. Chronic hyperglycemia initiates a cascade of interrelated metabolic disturbances including activation of the polyol, hexosamine, protein kinase C, mitogen-activated protein kinase, and advanced glycation end-product pathways, all of which converge to increase reactive oxygen species production, disrupt mitochondrial function, and overwhelm antioxidant defenses. These mechanisms lead to axonal degeneration, Schwann cell dysfunction, vascular impairment, and ultimately, irreversible nerve damage. At present, DPN remains largely untreatable, with available therapies offering only symptomatic relief. Increasing attention has been directed toward targeting the oxidative stress response as a potential disease-modifying strategy. Central to the antioxidant defence is the nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway signalling pathway, a critical regulator of cellular redox homeostasis. Current research highlights several therapeutic candidates including aldose reductase inhibitors, α-lipoic acid, benfotiamine, GLP-1 receptor agonists, DPP-4 inhibitors, and Nrf2 activators like curcumin and bardoxolone methyl, that aim to restore redox balance and mitigate neuronal injury. This review comprehensively discusses the molecular underpinnings of oxidative stress in DN and evaluates emerging antioxidant-based strategies that hold promise for preventing or slowing disease progression.