Non-invasive electrical stimulation restores corneal nerve density and sensory 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. Here we show that a non-invasive neural modulation therapy, transcutaneous electrical stimulation (ES), significantly restore 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 points to ion transport and Ca²⁺ signaling alteration. Consistently, membrane potential recording in TGs shows a rapid hyperpolarization upon ES accompanied by increased [Ca²⁺]_i level. Inhibition of potassium intermediate/small conductance calcium-activated channel (KCNN) abolishes the hyperpolarization and neural regeneration effect, whereas activation of KCNN channel significantly enhances nerve regeneration in the STZ model compared with sham treatment. Overall, ES restores corneal nerve density and function via KCNN activation in a diabetic mouse model, offering a novel, non-invasive, and clinically translatable therapeutic strategy for diabetic neuropathy.