PIEZO1: a mechanosensitive ion channel in the pathogenesis and pharmacotherapy of diabetic neuropathy

Diabetic neuropathy (DN) is a major and debilitating complication of diabetes mellitus, marked by progressive nerve dysfunction, chronic pain, and degeneration of both peripheral and autonomic neurons. Its complex pathophysiology involves persistent hyperglycemia, metabolic imbalance, vascular dysfunction, oxidative stress, and inflammation. Recent advances in mechanobiology have implicated that PIEZO1, a mechanosensitive ion channel, has emerged as a central player in mechanotransduction and is increasingly implicated in the pathophysiology of diabetic neuropathy. This review provides insights into the role of PIEZO1 in diabetic complications, particularly under conditions of chronic hyperglycemia, where its aberrant activation contributes to neuronal injury, oxidative stress, and inflammatory signalling. PIEZO1 modulates calcium influx in neurons, glia, endothelial cells, and immune cells, triggering downstream cascades that are intimately linked with neurodegeneration, chronic pain, and microvascular dysfunction. In diabetic neuropathy, PIEZO1 overexpression exacerbates nerve damage by disrupting Schwann cell function, impairing blood-nerve barrier integrity, and promoting neuroinflammation. Its expression in dorsal root ganglia further implicates it in the sensitization of nociceptive pathways and neuropathic pain. Beyond neural tissues, PIEZO1 modulate survival of pancreatic β-cell, endothelial responses to shear stress, and immune cell polarization, positioning it at the intersection of metabolic, vascular, and inflammatory networks. Emerging evidence from animal models and cellular studies underscores the therapeutic potential of PIEZO1-targeted interventions, including channel inhibitors like GsMTx4 and novel approaches such as electromagnetic field modulation. Given its broad mechanobiological significance and pathophysiological relevance, PIEZO1 represents a promising, multidimensional target for disease-modifying therapies in diabetic neuropathy and related chronic complications.