Targeting the HMGB1-TLR4 Axis Alleviates Neuropathic Pain-Associated Cognitive Deficits

Chronic neuropathic pain is frequently accompanied by debilitating cognitive deficits, yet the underlying mechanisms linking peripheral nerve injury to central nervous system dysfunction remain poorly understood, hindering the development of targeted therapies. This study identifies the HMGB1/ TLR4 signaling axis as a critical mediator driving these cognitive impairments. We demonstrate that HMGB1, released after nerve injury, activates hippocampal TLR4, triggering neuroinflammation, neuronal apoptosis, and synaptic deficits. Importantly, genetic deletion or neuronal-specific knockdown of TLR4, as well as pharmacological inhibition of the HMGB1/TLR4 interaction, rescues cognitive function. These findings elucidate a precise molecular pathway connecting peripheral neuropathic pain to cognitive decline and establish the HMGB1/TLR4 axis as a promising therapeutic target for preventing or treating pain-associated cognitive dysfunction.