iRhom2 deletion protects against diabetic neuropathy by suppressing neuroinflammation

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, characterized by progressive nerve damage and debilitating pain. Neuroinflammation plays a critical role in its pathogenesis, but therapeutic options remain limited. A disintegrin and metalloprotease 17 (ADAM17) regulates inflammatory signaling, but its ubiquitous expression makes it a difficult target. This study examined the role of inactive rhomboid protein 2 (iRhom2), a cofactor essential for ADAM17 activation, in the development of DPN. Diabetes was induced in wild-type (WT) and iRhom2 knockout (KO) mice using streptozotocin. Both groups developed hyperglycemia (>300 mg/dL); however, only WT mice exhibited significant mechanical and thermal hyposensitivity, characteristic of DPN. iRhom2 KO mice were protected from these deficits, suggesting a glucose-independent protective mechanism. In sciatic nerves of diabetic WT mice, expression of ADAM17, iRhom2, and tumor necrosis factor-α increased by 5.3-, 7.7-, and 48-fold, respectively; these changes were attenuated in KO mice. Histological analysis showed preservation of nerve fiber structure and reduced inflammatory infiltration in diabetic iRhom2 KOs. In cultured human microglial cells, high glucose triggered oxidative stress and induction of inflammatory mediators, including cyclooxygenase-2, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1. Silencing of iRhom2 reduced these responses. These findings identify iRhom2 as a critical mediator of diabetic neuropathy, acting by regulating neuroinflammation. Deletion of iRhom2 confers glucose-independent protection against neuropathic pain, highlighting iRhom2 as a promising therapeutic target for preventing or treating DPN. SIGNIFICANCE STATEMENT: This study identifies iRhom2 as a key mediator of diabetic peripheral neuropathy by driving neuroinflammation and oxidative stress. Deletion of iRhom2 provided protection against neuropathic changes, without altering glucose levels, revealing a glucose-independent mechanism. These findings establish iRhom2 as a promising therapeutic target, offering new translational opportunities to prevent or treat diabetic neuropathy.