Non-invasive electrical stimulation restores corneal nerve density and function in diabetic neuropathy via KCNN-dependent mechanism

Diabetic neuropathy (DN) is the most common complication of diabetes mellitus (DM) and often involves the cornea, where progressive loss of nerve fibers contributes to impaired corneal sensitivity and wound healing defects. Current treatments are limited, underscoring the need for a regenerative therapy. Transcutaneous electrical stimulation (ES) is a neural modulating therapy that non-invasively delivers microcurrent electricity to the eye via orbital skin. ES treatment significantly restored the nerve density and sensory function in both streptozotocin-induced DM mice and in vitro isolated trigeminal ganglia (TG) neurons. Transcriptomics analysis of TGs from in vivo ES pointed to ion transport and Ca ²⁺ signaling alteration. Consistently, membrane potential recording in TGs showed a rapid hyperpolarization upon ES accompanied by increased [Ca ²⁺ ] _i level. Inhibition of Ca ²⁺ -Induced K ⁺ Channel (KCNN) abolished the hyperpolarization and neural regeneration effect, whereas activation of KCNN channel significantly enhanced nerve regeneration in the STZ model compared with sham treatment. Overall, ES restores corneal nerve density and function in diabetes via KCNN activation, offering a novel, non-invasive, and clinically translatable therapeutic strategy for diabetic neuropathy.