Targeting the NLRP3 inflammasome alleviates the comorbidity of chronic pain and depression via enhancing the autophagy.

The comorbidity of chronic pain and depression exhibits the bidirectional relationship and forms a vicious cycle in disease development, diagnosis and therapy. NLRP3 inflammasome-mediated neuroinflammation is a crucial factor for the pathogenesis of pain and depression. The underlying mechanisms of NLRP3 in the comorbidity of chronic pain and depression is unclear. In this study the spared nerve injury (SNI) mouse model was constructed, NLRP3 level was pharmacologically (MCC950) and genetically (Nlrp3(−/−)) regulated. As a result, SNI surgery induced pain hypersensitivity, depression-like, motor impairment and cognitive dysfunction on mice. NLRP3 inflammasome was activated in the anterior cingulate cortex (ACC) of SNI mice. MCC950 administration and Nlrp3(−/−) increased the PWT values, prolonged the PWL times, increased the percentages of sucrose preference, shortened the immobility times, prolonged the fall latency time, increased the central and total distances, increased the cognitive index on SNI mice, additionally decreased the neuronal dysfunction and neuroinflammation, suppressed NLRP3 inflammasome activation and enhanced autophagy in ACC of SNI model mice and in the primary astrocytic cells. Thus, targeting the NLRP3 inflammasome improves chronic pain and depression via improving autophagy, neuronal dysfunction and neuroinflammation in ACC. This study provides the therapeutic targets for the comorbidity of chronic pain and depression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-35400-0.