EXPRESS: Nanoparticulate MgH₂ 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 (MgH2) on bone cancer pain (BCP).

Methods: A BCP model was established in Wistar rats. Daily oral dosing of 0.5% w/w MgH2 was administered. Assessment included pain sensitivity, motor coordination, and emotional behaviors. Hippocampal samples underwent RNA sequencing, Western blotting, immunofluorescence, and quantitative RT-PCR.

Results: MgH2 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, MgH2 served as an adjuvant to reduce opioid tolerance during fentanyl co-treatment, enabling lower opioid dosages. Collectively, MgH2 inhibited TRPM2 activation, microglial activation, oxidative stress, and NLRP3 inflammasome formation, which together reduced neuroinflammation and improved therapeutic outcomes.

Conclusion: MgH2 nanoparticles may relieve BCP and comorbid depressive symptoms by inhibiting TRPM2-mediated NLRP3 inflammasome activation in hippocampal microglia.