Nanoparticulate MgH 2 suppresses TRPM2-mediated NLRP3 inflammasome to relieve bone cancer pain

Background: Bone cancer metastases are the third most common site of cancer spread after lungs and liver. This condition often causes severe pain that impairs patients’ physical, psychological, and social well-being. We aimed to explore the potential therapeutic benefits of magnesium hydride (MgH 2 ) on bone cancer pain (BCP). Methods: A BCP model was established in Wistar rats. Daily oral dosing of 0.5% w/w MgH 2 was administered. Assessment included pain sensitivity, motor coordination, and emotional behaviors. Hippocampal samples underwent RNA sequencing, Western blotting, immunofluorescence, and quantitative RT-PCR. Results: MgH 2 markedly reduced mechanical hypersensitivity and depressive behaviors in rats with BCP. These effects were linked to suppression of the TRPM2–NLRP3 signaling axis in hippocampal microglia. Additionally, MgH 2 served as an adjuvant to reduce opioid tolerance during fentanyl co-treatment, enabling lower opioid dosages. Collectively, MgH 2 inhibited TRPM2 activation, microglial activation, oxidative stress, and NLRP3 inflammasome formation, which together reduced neuroinflammation and improved therapeutic outcomes. Conclusion: MgH 2 nanoparticles may relieve BCP and comorbid depressive symptoms by inhibiting TRPM2-mediated NLRP3 inflammasome activation in hippocampal microglia.