Modulation of ion channels as emerging therapeutic targets in the treatment of diabetic neuropathy

Diabetic neuropathy (DN) is a prevalent microvascular complication of diabetes mellitus, characterized by hyperalgesia and allodynia that severely impair quality of life. Current treatment approaches do not provide adequate relief, largely due to the multifactorial nature of disease pathogenesis. Growing evidence indicates that dysregulation of multiple ion channel families is a central mechanism underlying sensory neuron hyperexcitability and chronic pain in DN. This review comprehensively discusses the roles of major ion channel families, including voltage-gated sodium (Naᵥ), calcium (Caᵥ), and potassium (Kᵥ) channels, transient receptor potential (TRP) channels, purinergic receptors (P2X/P2Y), and mechanosensitive PIEZO (PIEZO 1 and PIEZO 2) channels, in sensory transmission and pain modulation. Their dysregulation, induced by chronic hyperglycemia and oxidative stress, promotes ectopic firing, altered calcium homeostasis, and glial activation, sustaining nociceptive hypersensitivity. The review further evaluates current and emerging ion channel-targeted therapeutic approaches, highlighting mechanistic insights, translational challenges, and future research directions. Recent research highlights multi-target and combination strategies, such as Naᵥ1.8 inhibition with KCNQ activation or concurrent blockade of TRPV1 and P2X3, as promising avenues offering synergistic analgesic benefits and disease-modifying potential. Advances in nanocarrier-based delivery, gene modulation, and patient-specific electrophysiological profiling further enhance translational prospects. Ultimately, the therapeutic landscape of PDN is shifting from single-channel blockade toward integrated approaches that modulate excitability, inflammation, and metabolic stress concurrently. Ion channels thus represent not only crucial mediators of PDN pathophysiology but also versatile therapeutic targets whose selective and combinatorial modulation may transform the management of diabetic neuropathic pain.