Autophagy-related pathway modulation is associated with hippocampal neuroinflammation and depressive-like behaviors in bone cancer pain mice.

Bone cancer pain (BCP) is a common and debilitating complication of primary bone tumors and bone metastases that is often accompanied by emotional disturbances and reduced quality of life. However, the hippocampal mechanisms underlying BCP-associated depressive-like behaviors remain unclear. In this study, a mouse model of BCP was established by intratibial inoculation of Lewis lung carcinoma cells. Behavioral assessments, immunofluorescence staining, ELISA, and Western blotting were performed to investigate changes in hippocampal inflammatory markers and autophagy-related protein expression. Rapamycin and 3-methyladenine (3-MA) were used to systemically modulate autophagy-related pathways pharmacologically. BCP mice exhibited significant mechanical hypersensitivity, reduced sucrose preference, and increased immobility time, accompanied by enhanced hippocampal microglial activation, elevated proinflammatory cytokine levels, and altered autophagy-related protein expression. In BCP mice, rapamycin treatment was associated with increased mechanical withdrawal threshold, increased sucrose preference, reduced immobility time, and reduced hippocampal inflammatory markers and NOD-like receptor family pyrin domain containing 3 (NLRP3) protein expression. In contrast, 3-MA treatment was associated with opposite changes in these behavioral and molecular measures. These findings provide pharmacological and molecular evidence that modulation of autophagy-related pathways is associated with coordinated changes in hippocampal inflammatory markers, NLRP3 protein expression, and behavioral phenotypes in BCP mice, thereby identifying a testable framework for future mechanistic studies.