Galectin-related protein, a key contributor, drives diabetes-associated neuropathic pain

Neuropathic pain associated with central sensitization is common in diabetic patients, but the underlying mechanisms remain unclear. Here, a proteomics screen identified a previously uncharacterized protein, galectin-related protein (LGALSL), which was significantly upregulated in cerebrospinal fluid and extracellular fluid of anterior cingulate cortex (ACC) in diabetes-related neuropathic pain model rats. Exogenous LGALSL administration reduced mechanical nociceptive thresholds by activating glutamatergic neurons in the ACC (ACCGlu). Chemogenetic manipulations and functional assays revealed that neuron-derived LGALSL directly binds to vimentin on ACC astrocytes, activating those astrocytes. These activated astrocytes subsequently maintain ACCGlu hypersensitivity, driving mechanical hypersensitivity in diabetic rats. Blocking LGALSL-vimentin interactions with a synthetic peptide alleviated LGALSL-induced mechanical hypersensitivity. This study establishes LGALSL-dependent astrocyte-mediated hyperactivation of ACCGlu neurons as a new pathological mechanism of neuropathic pain in diabetes.