1. 2026;29;E55-E69SIRT1 Facilitates Beclin-1 Nuclear Translocation to Mitigate Nociceptive Hypersensitivity in Rats with Bone Cancer Pain by Restoring Autophagic Flux
   Animal Study
   Qiuli He, MD, Wenjie Li, MB, Cuie Deng, MB, Zhiming Zhang, MD, and Housheng Deng, MD.

BACKGROUND: The etiology of bone cancer pain (BCP) is multifaceted, and effective therapeutic strategies for treating the condition remain elusive. Prior research has implicated sirtuin 1 (SIRT1) in the pathogenesis of BCP, suggesting the protein’s potential to modulate autophagy and mitigate nociceptive sensitization; however, the underlying mechanisms of BCP are not fully understood. 

OBJECTIVES: This study aimed to elucidate the role of SIRT1 in activating autophagy and its impact on the development of nociceptive hypersensitivity in a rat model of BCP. 

STUDY DESIGN: Controlled animal study. 

SETTING: Female Sprague Dawley® rats weighing 180–220 g were used. 

METHODS: The BCP model was established by a single injection of Walker 256 breast cancer cells (10 µL, 107cells/mL) into the tibia. Mechanical pain sensitivity was assessed behaviorally using an Electronic von Frey Anesthesiometer. 

RESULTS: Western blot (WB) analysis revealed reduced SIRT1 levels and elevated beclin-1 expression, an increased LC3II/LC3I ratio, and enhanced P62 expression in the dorsal horns of spinal cord tissues from rats with BCP. Immunofluorescence assays demonstrated co-localization of SIRT1 with neuronal cells and beclin-1. Subsequent experiments indicated that intrathecal administration of a SIRT1 agonist in rats with BCP postponed the downregulation of SIRT1, decreased the acetylation of beclin-1, and facilitated beclin-1 nuclear translocation. This treatment also led to a reduction in the LC3II/LC3I ratio and P62 expression levels. Collectively, these findings suggest that SIRT1 may ameliorate nociceptive hypersensitivity in rats with BCP through the promotion of beclin-1 nuclear translocation, thereby restoring autophagic flux.

LIMITATIONS: This study focused on peripheral/spinal mechanisms but not supraspinal/cortical contributions. Pharmacological tests were limited to a single time point, potentially missing dynamic pain changes during tumor progression. Nevertheless, the findings of this study offer valuable preliminary insights. 

CONCLUSION: This research uncovers a novel mechanism of SIRT1 in the genesis of nociceptive hypersensitivity in BCP and offers potential avenues for therapeutic intervention.

KEY WORDS: SIRT1, beclin-1, autophagic flux, bone cancer pain