• MOTS-c, a mitochondrial-derived peptide, significantly alleviates bone cancer pain and bone destruction in a mouse model.
• The analgesic effect of MOTS-c is mediated via AMPK activation, restoring mitochondrial biogenesis, and suppressing microglial activation and inflammatory factors in the spinal cord.
• Peripherally, MOTS-c modulates osteoclast and immune cell function in the tumor microenvironment, providing long-term pain relief.
• Chronic MOTS-c administration shows minimal side effects on liver, renal, lipid, and cardiac functions, supporting its safety as a therapeutic candidate.