Hinokitiol alleviates neuropathic pain and modulates Nrf2/HO-1 and NLRP3 inflammasome signaling.

Neuropathic pain (NP) is a chronic and debilitating condition that results from peripheral or central nervous system injury and is characterized by hyperalgesia and abnormal pain sensations. Current treatments are often ineffective and associated with significant side effects. This study investigated the therapeutic potential of hinokitiol (HIK) in chronic constriction injury (CCI)-induced NP and examined its association with oxidative stress and neuroinflammatory signaling. Network pharmacology identified NFE2L2 (Nrf2) as a candidate node, while molecular docking predicted a possible HIK-Nrf2 interaction; these computational findings were used for hypothesis generation rather than as evidence of direct physical binding. In vivo, HIK significantly alleviated mechanical allodynia and thermal hyperalgesia in CCI rats, reduced spinal microglial activation, and decreased markers associated with NLRP3 inflammasome activation and pyroptotic signaling. In LPS/ATP-stimulated BV2 cells, HIK promoted Nrf2 nuclear accumulation and HO-1 expression, reduced ROS accumulation, and attenuated inflammasome- and pyroptosis-associated markers. Pharmacological Nrf2 inhibition with ML385 partially weakened the effects of HIK, supporting the involvement, but not exclusive mediation, of Nrf2 signaling. Collectively, the findings indicate that the analgesic effects of HIK are associated with modulation of the Nrf2/HO-1 and NLRP3 inflammasome-related pathways. Further target-engagement, pathway-specific rescue, sex-inclusive, and primary-cell studies are required to establish direct molecular targets and causal cell-specific mechanisms.